More Evidence that Sinemet and Madopar are Not Toxic and do Not Accelerate Disease Progression

You can find out more about NPF's National Medical Director, Dr. Michael S. Okun, by also visiting the NPF Center of Excellence, University of Florida Center for Movement Disorders & Neurorestoration.

Many Parkinson’s disease patients and families members have been unnecessarily alarmed by the continuing reports that Sinemet and/or Madopar (European Sinemet) may accelerate disease progression, and that doses and drug intervals should be limited. These reports have unfortunately been fueled by sparse human evidence. Patients need to be aware that dopamine replacement therapies such as Sinemet and Madopar remain the single most effective, and single most important treatment for Parkinson’s disease worldwide. This month’s “What’s Hot” column will focus on the evidence including the most recent paper on this important topic.

In this month’s issue of Neurology, important evidence is presented that dopamine replacement therapy is not toxic, and does not accelerate disease progression. Parkkinen and colleagues at Queen Square in London examined pathology in 96 post-mortem Parkinson’s disease brains, and paired the tissue with clinical information including levodopa use. The study concluded that in the human condition “chronic use of L-dopa does not enhance progression of Parkinson’s pathology.”

In an accompanying editorial, two prominent neurologists in the field pointed out that there “remains lingering concerns as to whether levodopa is toxic to dopamine neurons and accelerates the degenerative process.” The science quoted to support these claims has included levodopa undergoing auto-oxidation, and forming reactive oxygen species and toxic protofibrils. Additionally, the science includes a classical experiment that showed when levodopa was mixed with brain cells placed in a dish, there was toxicity.
The research, however, has fallen short in demonstrating toxicity of the drug in the human form of Parkinson’s disease. In fact, there now exists broad levels evidence from many studies across many countries (including most recently the ELLDOPA study) that levodopa is extremely beneficial to the human patient, and that levodopa has had a positive effect on disease course. (my own note here: this "recent" study was published in 1999)

Sinemet was recently reported as the most commonly administered drug among 4000+ patients being followed longitudinally in the National Parkinson Foundation Quality Improvement Initiative study. Expert practitioners who reported in this database, utilized levodopa more than any other drug-- including dopamine agonists, and they used levodopa more (not less) as disease durations increased.
(I'm not sure what the author thinks this is supposed to indicate)

Just saying.....

My thanks go to Benjamin Stecher on PRIG who has pointed us to an important paper that has been published in the NEJM. It attempts to answer the question of whether PwP (People with Parkinson's) should be prescribed levodopa soon after diagnosis or whether its use should be delayed, being saved for later when it is really needed. (Levodopa is the main component in Sinemet, Madopar and Stalevo.)

446 PwP were in the trial. They were placed in one of two cohorts: one took levodopa from the beginning through to 80 weeks; the other took placebo up to 40 weeks and were then moved onto levodopa for the final 40 weeks.

As you might expect, in the first half the levodopa group did better than the placebo group, but in the second half, when both groups were on the same amount of levodopa, there was no statistically significant difference between the two groups.

My take on the result is that it tips the balance to slightly higher doses. If you spend much of the day "off" and if you don't have dyskinesia, you should discuss with your doctor whether more medication is required.

Reference:

[1] "Randomized Delayed-Start Trial of Levodopa in Parkinson’s Disease
Constant V.M. Verschuur, M.D., Sven R. Suwijn, M.D., Judith A. Boel, Ph.D., Bart Post, M.D., Ph.D., et al., for the LEAP Study Group
N Engl J Med 2019; 380:315-324
https://www.nejm.org/doi/full/10.105...kYb_bdtJoa3EQA

John