Levodopa Best Choice for Initial Parkinson's Treatment

Dr. Richard Gray









Dr. Richard Gray


Levodopa Best Choice for Initial Parkinson's Treatment

Pauline Anderson

June 11, 2014


The overall balance of risks and benefits favors levodopa over levodopa-sparing therapies for patients with newly diagnosed Parkinson's disease (PD), according to a study that showed levodopa had better patient-rated quality of life both in the short and long term.

The study — the largest drug trial to date in PD — also found that initial treatment with a monoamine oxidase type B inhibitor (MAOBI) was at least as effective as a dopamine agonist.


These results are clinically meaningful, said study author Professor Richard Gray, University of Oxford, Oxford, United Kingdom, who was director of the University of Birmingham Clinical Trials Unit at the time of the study.


"We showed that the balance favored levodopa; it's only a small difference, but it's a very clear difference on quite a range of outcome measures, and, of course, levodopa is very inexpensive" compared with the alternative drugs, he told Medscape Medical News.


Drug trials comparing dopamine agonists with levodopa over the last 10 to 15 years have reported more dyskinesia with levodopa, so physicians have been moving toward dopamine agonists instead. However, Professor Gray pointed out that dopamine agonists have their own adverse effects."I think we have put too much emphasis on dyskinesia at expense of the other ones," he said.


The results are published online June 10, 2014 in The Lancet.



PD MED Trial

The open-label PD MED trial randomly assigned 1620 mostly British patients with early PD to receive either levodopa or 1 of 2 levodopa-sparing approaches: a dopamine agonist (eg, ropinirole or pramipexole) or an MAOBI, such as oral or sublingual selegiline, or rasagiline. Investigators and patients were not masked to group assignment.


According to the study design, investigators could start open-label treatment with whichever drug they preferred within the allocated class and to titrate the dose of levodopa and dopamine agonists within the bounds of the product license. If symptoms weren't controlled by the standard dose of MAOBI or the maximum tolerated dose of dopamine agonist, investigators could add levodopa as needed.


During follow-up, the PD diagnosis was revised for 5% of patients. Missing assessments did not significantly differ between groups.

Participants taking an MAOBI or dopamine agonist were significantly more likely to discontinue their allocated drug class than those allocated to levodopa. Seven-year probabilities were 72% for MAOBI, 50% for dopamine agonists, and 7% for levodopa (P < .0001).


he researchers found that after about 7 years of follow-up, patients assigned to levodopa scored on average 1.8 points higher on the mobility subscale of the 39-item Parkinson's Disease Questionnaire (PDQ-39) than those assigned to levodopa-sparing therapy (95% confidence interval [CI], 0.5 - 3.0). The PDQ-39 assesses the effect of PD on quality of life and is sensitive to changes considered important to patients but not identified by clinical rating scales.


The study also found that levodopa came out on top on a range of other patient-rated outcome measures, including activities of daily living, cognition, communication, bodily discomfort, and the summary index, which is an overall score for the 10 PDQ-39 domains. The levodopa group averaged 1.0 point higher on this index than did the levodopa-sparing group (95% CI, 0.3 - 1.7; P = .008).


However, the 1.8 points on the PDQ-39 mobility and the 1.0 point on the summary index favoring initial levodopa were below the predefined 6-point threshold believed to be the minimum clinically important difference when the PD MED was designed, said the authors.

"Expressed in relation to rate of decline, these treatment benefits correspond to around 5 months and 4 months progress of the disease, respectively — less than the 6-month disease progress MCID [minimum clinically important difference] threshold cited in dementia studies using annual decline methods," the authors write. "Thus, the benefits of levodopa compared with levodopa-sparing are unquestionably small."



More Dyskinesia

Even though patients in the levodopa group reported benefits in many areas, they were more likely to develop dyskinesia than were those in the other groups (hazard ratio, 1.52; 95% CI, 1.16 - 2.00; P = .003).


"What this probably means is that early in the disease, developing dyskinesia isn't too serious; you can adjust the medication and minimize the impact it has on the patient," said Professor Gray. "I think perhaps that the impact of dyskinesia isn't as big as perhaps has been made out," and that other adverse effects may be more important.


Adverse effects that patients may consider more important than dyskinesia may include sleep disturbances, edema, and compulsive behavior that has been linked to dopamine agonists, he said.


Clinician-rated disease status by Hoehn and Yahr staging was also significantly improved with levodopa — on average 0.7 point better than with the alternate therapies (95% CI,

0.3 - 0.12; P = .0009), the study found.


The study results suggest that there are no grounds for concern that levodopa as a first-line therapy results in worse long-term outcomes, commented Professor Gray.

"Looking at all the measurements of cumulative damage — neurodegeneration, people needing institutional care, developing dementia, which is very common in people with Parkinson's disease, and survival — all of those favored levodopa over dopamine agonists. So I think it's now not really tenable to believe that dopamine agonists will be neuroprotective or, on the opposite side of the equation, that levodopa will increase the rate of degeneration and damage."


Although more patients discontinued MAOBIs than dopamine agonists, the researchers noted small (below MCID thresholds) but significant benefits favoring initial treatment with MAOB1 compared with dopamine agonists in PDQ-39 mobility, cognition, and summary index scores. This result, said Professor Gray, "was definitely surprising" because "nobody really expected the MAOB inhibitors would be as good a dopamine agonists, and it turned out that they were a little bit better."


The study found no difference in treatment efficacy in patients younger and older than 70 years. The researchers also looked at those under 60, but it was too small a group to be meaningful, said Professor Gray. "We thought that the over and under 70 was a more reliable result to report than the small under 60 subgroup."


The authors will do a full cost utility analysis separately, but because outcome measures such as admission to institutions and development of dementia, which are major cost drivers, consistently favored levodopa in this analysis, the economic analyses will likely favor the substantially less expensive levodopa therapy. And that analysis will also probably favor MAOBIs, particularly selegiline, which cost less than dopamine agonists, said the authors.


Professor Gray is convinced the study results will change prescribing habits. He did a survey of British movement disorders specialists before and after presenting the study findings for the first time and found a "dramatic switch." For example, before the presentation, 63% of the specialists favored a dopamine agonist as initial therapy in patients under 60 years old, and only 10% levodopa, but after hearing the results, 21% indicated they would choose a dopamine agonist and 34% levodopa.


Levodopa Phobia


In an accompanying editorial, Anthony E. Lang, MD, and Connie Marras, MD, PhD, the Edmond J. Safra Program in Parkinson's Disease, University Health Network, Toronto, Ontario, Canada, noted that although the differences in favor of initial levodopa treatment were "significant and persistent," they were "very small" and failed to even approach the study's predetermined minimum clinically important differences, defined as 6 points on the PDQ-39 mobility subscale.


An important study finding, they said, was that patients receiving levodopa did as well as or better than others despite the greater incidence of involuntary movements.

An "unexpected" study result was the persistence of a small but statistically significant difference between outcomes in the levodopa group vs levodopa-sparing groups for as long as 7 years, with no suggestion of a reduction in size of this difference with time, they point out.


"This finding is surprising in view of the progressive adoption of levodopa treatment in the sparing groups," they write. "This observation suggests that either the difference in outcomes is driven largely by adverse effects of dopamine agonists, which are often continued in the presence of the added levodopa, or that there is a barrier to achievement of true clinically equivalent efficacy."


In the absence of a clear explanation, a careful examination of the baseline characteristics of patients lost to follow-up vs those continuing, and the reasons for dropout, would be important, they note.


Younger age is perhaps the most important predisposing factor for levodopa-induced dyskinesia, so clinicians question how best to initiate treatment in this younger age group. While the authors stratified patients into those younger and older than 70 years, "[i]n view of the present state of clinical uncertainty, examination of the group of patients younger than 60 years could have been more interesting."


The editorial writers note several changes since the PD MED was initiated in 2000. For example, it's now generally acknowledged that a delay or reduction in dyskinesia through initiation of dopamine agonists as opposed to levodopa in the early years, when symptoms are mostly mild, doesn't necessarily translate into a better outcome in the long term.

As well, reports of impulse control disorders with dopamine agonists surfaced only after PD MED was started. "It is now widely recognised that this is a major limitation to dopamine agonist therapy that has a strong effect on the choice of these drugs as initial therapy."


The editorial writers discuss the "levodopa phobia" or the reluctance to use levodopa because of a concern that it's toxic to remaining dopaminergic neurons. These fears have largely dissipated, but there remains the established concern about increased risk of motor complications.

This new study, they write, "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."


The study was supported by the United Kingdom National Institute for Health Research Health Technology Assessment Programme and Department of Health. Professor Gray has disclosed no relevant financial relationships. Dr. Lang has received payment for consulting from Ceregene, Novartis, Teva, Abbvie, Allon Therapeutics, Merck, Medtronic, Avanir, Biogen Idec and Neurophage. Dr. Marras has received payment for speaking from EMD Serono.


Published online June 11, 2014.




Observations on the above study by Dr. Robert Hauser .....

The results of the PD MED study are not terribly surprising. It is well known that levodopa is the most effective antiparkinsonian medication with the greatest benefit for mobility and overall quality of life. What is debated is whether young patients, who are at the highest risk of developing motor complications (motor fluctuations and dyskinesias) benefit in the long run through the use of levodopa sparing strategies (ie using MAO-B inhibitors or dopamine agonists as initial dopaminergic therapy).

In the PD MED study, the benefit seen with levodopa compared to the levodopa sparing strategies was quite small and did not meet or exceed the minimal important difference. Thus, the main conclusion is that self-reported mobility (mobility dimension on the PDQ-39) as well as overall quality of life and individual components of quality of life were not meaningfully different based on the initial treatment assignment.

Notably, the patients assigned to the levodopa group were observed to receive significantly greater levodopa equivalent dosages of PD medication at one year and this might contribute to the small benefit observed in the levodopa group. Moreover, the calculations used to derive levodopa equivalents are based on clinical observations and are not necessarily exactly correct, especially when dealing with combinations of medications and different stages of disease. If one were to accept the notion that at 5-6 years, the groups are essentially comparable clinically, and calculate new conversion factors for levodopa equivalents based on the data from PD MED, this recalculation would suggest that conversion factors used for dopamine agonists are too high, and the new conversion would suggest that patients in the levodopa group were on higher dosages of medication for several years (rather than just one). This is highly theoretical but highlights the potential role of dosing differences across groups.

The PD MED trial also found that patients in the levodopa group were significantly more likely to develop dyskinesia than those in the levodopa sparing groups (HR=1.52, p=0.003). This finding is also not unexpected. But the critical question is “Is there a group of patients for whom the dyskinesia inducing effect of levodopa outweighs its small benefits as an initial antiparkinsonian medication, such that we should use other medications first?” Unfortunately, this is where the PD MED trial falls short. It is younger patients who are most prone to develop dyskinesia and therefore it is for those patients we seek an answer. However, the average age of participants in PD MED was close to 70 years, and only 12% were younger than 60 years. Unfortunately, we are not provided with a sub-analysis of this younger age group even though these are the patients in whom movement disorders experts tend to initiate dopaminergic therapy with levodopa sparing medications. Perhaps such an analysis will be forthcoming in the future.

Thus, the PD MED study is consistent with today’s thinking and not likely to alter prescribing habits. There has been a trend for decreasing dopamine agonist use based on recognition of side effects such as sudden onset sleep and impulse control disorders, and a reduction in MAO-B usage based on lack of clear evidence of a disease modifying effect. In patients over 70 years of age, levodopa is the principal treatment for most. In patients under 60 years of age, levodopa sparing strategies are commonly employed and delay the onset of dyskinesia, but whether this confers a meaningful long term benefit remains unclear.

Robert A. Hauser, MD, MBA

Professor of Neurology, Molecular Pharmacology and Physiology
Director, USF Health Byrd Parkinson’s Disease and Movement Disorders Center of Excellence
National Parkinson Foundation Center of Excellence

Tampa, FL 33613  USA


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