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Largest Clinical Trial of Three Different Types of Drugs Finds Levodopa Therapy Most Effective to Start for Parkinson's Disease



CIRCUITS OF THE BASAL GANGLIA in treatment of Parkinsons disease. Levodopa, dopamine agonists and MAO-B inhibitors stimulate excitatory signals from the thalamus to the cortex by effects on the striatum, compensating for decreased dopaminergic signals from substantia nigra (seen at bottom right). Picture shows 2 coronal slices that have been superimposed to include the involved basal ganglia structures. Plus (+) and minus (-) signs at the point of the arrows indicate respectively whether the pathway is excitatory or inhibitory in effect. Green arrows refer to excitatory glutamatergic pathways, red arrows refer to inhibitory GABAergic pathways and turquoise arrows refer to dopaminergic pathways that are excitatory on the direct pathway and inhibitory on the indirect pathway.

In one of the largest randomized trials to compare three different classes of Parkinson's disease drugs, investigators found that levodopa achieves somewhat better control of motor symptoms of Parkinson's disease than do dopamine agonists and monoamine oxidase type B inhibitors.

Initial treatment with levodopa appears to have persistent benefits over levodopa-sparing therapy in Parkinson's disease (PD) on patient-rated mobility scores, according to a report published online in The Lancet on June 11.

One of the largest randomized controlled trials to compare levodopa, dopamine agonists, and monoamine oxidase type B inhibitors (MAO-BIs) for overall quality of life turned up what may be considered a surprising result: newer is not always better.

“We found that when we asked patients with Parkinson's disease how their drugs affected their overall quality of life, the older drug levodopa was better than newer, more expensive drugs and that this benefit persisted for at least seven years from starting treatment,” Richard Gray, a professor in the Medical Statistics Clinical Trial Service Unit of the University of Oxford and first author of the study by the UK Parkinson's Disease MED Collaborative Group, told Neurology Today. “The old drug levodopa is still the best initial treatment strategy for most patients and it costs less.”

The study involving more than 1600 patients offered some clarity about conflicting benefits and downsides associated with the three classes of drugs widely used as initial therapy in PD. Levodopa achieves somewhat better control of motor symptoms of Parkinson's disease than do dopamine agonists and MAO-BIs, the study authors wrote, but dyskinesias and fluctuations in motor control develop after long-term use or high-dose treatment.

Motor complications are seen less frequently with dopamine agonists and MAOBIs than with levodopa, suggesting that longer-term symptomatic control could be better with levodopa-sparing therapy than with levodopa. However, non-motor side effects such as nausea, hallucinations, edema, and sleep disturbance are more frequent with dopamine agonists than with levodopa and could be more important for patients and caregivers than are motor complications.


In the study, 1620 patients were assigned to study groups between 2000 and 2009: 528 to levodopa, 632 to dopamine agonists, 460 to MAO-BIs. Patients and investigators were not masked to group assignment. Primary outcomes were the mobility dimension on the 39-item patient-rated Parkinson's disease questionnaire (PDQ-39) quality-of-life scale — which ranges from 0–100, with six points defined as the minimally important difference — and cost-effectiveness.

With a three-year median follow-up, PDQ-39 mobility scores averaged 1.8 points better in patients randomly assigned to levodopa than those assigned to levodopa-sparing therapy (95% CI 0.5–3.0), with no increase or attrition of benefit during seven years' observation. Of 632 patients who were in the dopamine agonists group, 179 discontinued treatment because of side effects, while 104 (23 percent) of 460 patients taking MAO-BIs discontinued treatment. This compares with just 11 (2 percent) of 528 patients given levodopa (p<0.0001).

On another outcome, quality of life years (Qol) years, derived from the Euro Qol (EQ-5D) scores — a standardized measure of patient-reported overall health — patients averaged 0.03 (95% CI 0.01–0.05; p=0.0002) better with levodopa than with levodopa-sparing therapy.

Patients in the levodopa group were more likely to develop dyskinesias than those in the levodopa-sparing group, but there was no difference in motor fluctuations. Fewer patients in the levodopa than in the levodopa-sparing group developed dementia, entered institutional care or died, but none of these differences were statistically significant.

PDQ-39 mobility scores averaged 1.4 points better in patients initiating therapy with MAO-BIs than those initiating dopamine agonists. Significantly better scores on the cognition subscales were also seen with MAO-BIs compared with dopamine agonists.

The study authors noted that they will be reporting separately a full cost-utility analysis of the different therapeutic options.


Lisa M. Shulman, MD, FAAN, a professor of neurology and director of the University of Maryland Parkinson's Disease & Movement Disorders Center, called the report a well-designed study with unexpected findings. “For years levodopa-sparing therapy has been promoted to reduce motor fluctuations and dyskinesias, and even to avoid `levodopa toxicity,'” she told Neurology Today. “However, this study shows better outcomes with initiating therapy with levodopa compared to either dopamine agonist or MAO-B inhibitors. The advantages of initiating therapy with levodopa were wide-ranging, including better mobility, activities of daily living, communication, and summary scores on the PDQ-39.”

She added that patients initiating therapy with agonists or MAO-B inhibitors were also more likely to discontinue these drugs or to add another drug. “Patients in the levodopa group were more likely to develop dyskinesias but there was no difference in motor fluctuations,” Dr. Shulman said. “An important caveat is that the median follow-up was three years, but the majority of clinically significant motor complications emerge later.”

Charles Adler, MD, PhD, FAAN, a professor of neurology at Mayo Clinic College of Medicine in Scottsdale, AZ, emphasized that though there were statistically significant differences favoring initial levodopa treatment, there were relatively small differences in benefit between the therapies. He said there is little surprise regarding the efficacy of MAO-BIs, but he added that “otherwise the data show the benefit of all the medications as measured by the patient subjective measure.”


RICHARD GRAY: “We found that when we asked patients with Parkinsons disease how their drugs affected their overall quality of life, the older drug levodopa was better than newer, more expensive drugs and that this benefit persisted for at least seven years from starting treatment. The old drug levodopa is still the best initial treatment strategy for most patients and it costs less.”

“The trend in the US over the past few years has been that starting any of the drugs for PD is reasonable and the only possible advantage of a dopamine agonist first strategy in younger PD patients may not truly have an advantage based on this study,” Dr. Adler said. “But the idea the newer drugs may not be better than the use of levodopa as first line therapy is true.”

“I think that it is important for the treating physician to realize that there is now sufficient data to support using levodopa first in any patient with PD but that they also would not be incorrect if they chose to use a dopamine agonist or a MAO-BI first,” he continued. “Most importantly, the physician and the patient should work as a team in finding the right combination of medications for the patient to feel as optimal as possible and that over time the patient will likely need multiple medication adjustments with polypharmacy being anticipated.”

In an accompanying editorial, Anthony E. Lang, MD, professor in the department of medicine (neurology) at the University of Toronto and the Jack Clark chair for Parkinson's Disease research at the University of Toronto, and Connie Marris, PhD, an assistant professor of neurology at the University of Toronto, wrote that the findings of the current study may provide reassuring “data showing that in most patients with Parkinson's disease, who have an older age of onset, how treatment is initiated generally does not matter because outcomes are very similar.” But, they wrote, the question of how best to initially manage young patients with Parkinson's disease remains unresolved.

They added: “The results of the cost analysis will add another important factor for physicians to weigh when judging how to initiate treatment...the results of this study will help to persuade physicians 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 PD MED Collaborative Group. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): A large, open-label, pragmatic randomized trial. Lancet 2014; Epub 2014 Jun 11.
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