Levodopa Shows Slight Edge as Initial Treatment for Parkinsons

- Jun 10 2014

People who took levodopa (which is usually prescribed as Sinemet®) as their initial therapy after a Parkinson’s disease (PD) diagnosis reported, over the long term, slightly better mobility and quality of life than those who began treatment with other classes of PD drugs. The results from the largest clinical trial comparing these treatments, which appear in the June 11 online edition of The Lancet, indicate that those who started PD treatment with levodopa reported slightly better results than those who began treatment with either dopamine agonists, such as ropinirole (Requip®) or pramipexole (Mirapex®), or monoamine oxidase type B (MAO-B) inhibitors, including selegiline (Eldepryl®) or rasagiline (Azilect®).

There has been disagreement about which treatment for Parkinson’s is most beneficial as an initial therapy. Some people with Parkinson’s and their doctor opt for levodopa, which has long been the gold standard therapy and which provides the best relief for movement symptoms as the disease progresses. But after taking this drug for five or more years, about a quarter of people develop involuntary movements, called dyskinesias. Furthermore, there had been some concern (which has since been refuted in the PDF-funded study, ELLDOPA) that the drug might be toxic to brain cells. Some people with PD and their doctors, in an attempt to avoid negative long-term impact and potentially delay dyskinesias, have opted to first take alternatives to levodopa — drugs known as dopamine agonists and MAO-B inhibitors. But dopamine agonists can lead to side effects including nausea, hallucinations, swelling of the legs, sleep difficulties, and impulse control disorders. And MAO-B inhibitors have only a modest impact on motor symptoms.

Dozens of researchers, working together as the United Kingdom PD MED Collaborative Group, set out to discover which of the three classes of drug leads to the best outcomes for people with PD, both in the short term and over the course of several years. The study authors recruited 1,620 people with early stage PD to participate in a clinical trial.  They randomly assigned roughly one-third of the study participants to receive only one of the three therapy types – levodopa, dopamine agonists or MAO-B inhibitors – as their first PD medication. The study was open-label; meaning that the medical personnel and the people being treated all knew which therapy was being given. At baseline, and at regular intervals up to seven years after starting treatment, study participants filled out standard evaluations of mobility, quality of life, and cognition.

Results

  • People taking levodopa consistently reported a very small, but statistically significant better quality of life and milder motor symptoms than people taking other treatments, both soon after beginning therapy and in the long term, up to seven years.
  • People initiating treatment with MAO-B inhibitors reported slightly more improvement in mobility than those who started with dopamine agonists.
  • Side effects led some participants to drop out of the study, including 28 percent of participants taking dopamine agonists, 23 percent of those taking MAO-B inhibitors, and two percent of those taking levodopa.
  • The researchers did not observe any decline in levodopa’s benefit. There was no evidence for cumulative adverse effects the group treated with levodopa when compared with those treated with dopamine agonists or MAO-B inhibitors.
  • Over time, nearly all those who were only taking MAO-B inhibitors or dopamine agonists were also taking levodopa as part of their PD medications.

What Does It Mean?

The current study aimed to answer an unresolved question in the treatment of PD, which is: what class of drug is most effective for people with Parkinson’s just beginning treatment? The researchers compared three widely-used classes of treatments – levodopa, dopamine agonists and MAO-B inhibitors – to see which one is the best option.

The study found that levodopa works slightly better than MAO-B inhibitors or dopamine agonists as an initial therapy for people with PD. Participants treated with levodopa reported milder motor symptoms and slightly better quality of life than people taking other treatments.  However, it should be noted that the differences were so mild that regardless of which therapy a person took first, the effects were very similar long-term.  No medically significant short- or long-term benefit was found for initiating therapy with levodopa or one of the alternatives to dopamine.

When the overall benefits and risks are considered, the study authors nevertheless suggest that levodopa may be the best initial and long-term therapy for people with PD.

What are the take-home messages from this study? First, the fear that people have surrounding levodopa continues to be unfounded. People who took levodopa as an initial therapy in this study developed dyskinesias at nearly the same rate as those who started with the other PD medications. Second, for the seven-year duration of this study, levodopa did not appear to lose its effectiveness nor did it appear to speed disease progression. Third, because MAO-B inhibitors and dopamine agonists are typically more expensive than levodopa, people can confidently make choices based upon cost as well as effectiveness.  It is also important to note that all study participants were eventually treated with levodopa regardless of initial therapy assignment.

The major strengths of the current study are its large number of participants and the long duration of follow up. Its major limitations are that people with PD and practitioners were not blinded to the treatment arm. Additionally, since the majority of people in this study were 60 years or older, one unanswered question is which therapy is best for treating people who live with young-onset PD.

All in all, the end result of this study should lay to rest the concerns about levodopa. These results should allow people with Parkinson’s and their physicians to choose therapies that make sense clinically as well as financially.

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Reference: PD MED Collaboration Group. (2014) 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 randomised trial. The Lancet: 1–13. DOI: 10.1016/S0140-6736(14)60683-8  http://dx.doi.org/10.1016/S0140-6736(14)60683-8

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