Levodopa and Not Dopamine Agonists as the Initial Therapy for Parkinson's Disease: Mounting Evidence
This is an article from my What's Hot blog at National Parkinson's Foundation but I thought so important that I would repost here for the readers.
In November 2011 we wrote about an important phenomenon called levodopa phobia, or avoidance of dopamine as a treatment for Parkinson’s disease. 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 update the previous 2011 column, and focus on the new evidence published in the Lancet this month by the PD MED Collaborative Group.
Neurology previously published an article in 2011 citing that there was important evidence 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. 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. Sinemet was recently reported as the most commonly administered drug among 7000+ 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.
The newest study published in this month’s Lancet included newly diagnosed patients randomized to receive a dopamine agonist, a monoamine oxidase inhibitor (MAOBI) or levodopa. The primary outcome was the mobility dimension on the Parkinson’s disease questionnaire (PDQ-39) quality-of-life scale which is a validated way to measure meaningful improvements. There were 1620 patients randomized and followed. The three year follow-up revealed the PDQ-39 mobility scores were better in levodopa as compared to the other two groups. Follow-up at 7 years revealed levodopa was the best therapy, but there was a small difference favoring initial therapy with the MAOBI when this drug was compared to a dopamine agonist. The treatment related side effects were less in levodopa.
Over the past two decades the trendy phenomenon, referred to as levodopa phobia (intentionally avoiding prescriptions for levodopa) likely impeded the best clinical care for many Parkinson’s disease patients. An accompanying editorial to the recent Lancet article pointed out that levodopa phobia and also the favoring of agonist therapy was primarily driven by aggressive pharmaceutical marketing. The Lancet study revealed that all three therapies should be considered, but ultimately that the choice of drugs should be tailored to the individual patient. Patient-rated mobility in this study clearly favored initial levodopa therapy.
What all this adds up to for patients and for Parkinson’s sufferers is that Sinemet and Madopar should be considered safe and effective as initial treatments for Parkinson’s disease. The doses and intervals should be frequently adjusted by an experienced neurologist/practitioner in order to maximize benefits, and to tailor to individual symptoms. Patients and families should keep in perspective that the “talk” about levodopa being toxic and accelerating disease progression (levodopa phobia) can prove a major distractor to good care practices. Precious minutes in the doctor-patient relationship should not be wasted on these claims, and prescribers should not avoid or under-dose this critical therapy, especially in patients with treatable symptoms. Critics of Sinemet and Madopar will need to bring forward much stronger human data if they wish to change clinical practice. In the mean time, we need to serve our patients by sharing with them the weight of the evidence which strongly supports that levodopa replacement therapy is not toxic, does not accelerate Parkinson’s disease, and can be used safely as initial therapy.
Selected References:
Parkkinen L, O'Sullivan SS, Kuoppamäki M, Collins C, Kallis C, Holton JL, Williams DR, Revesz T, Lees AJ. Does levodopa accelerate the pathologic process in Parkinson disease brain? Neurology. 2011 Oct 11;77(15):1420-6. Epub 2011 Sep 14.
Olanow CW, Obeso JA. Levodopa toxicity and Parkinson disease: Still a need for equipoise. Neurology. 2011 Oct 11;77(15):1416-7. Epub 2011 Sep 14.
Fahn S. Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Earlier vs Later L-DOPA. Arch Neurol. 1999 May;56(5):529-35.
Okun MS. An Important Update for Clinicians Treating Parkinson’s Disease Patients: Is This the End of Levodopa Phobia. New England Journal of Medicine Journal Watch, June, 2014.
Kurlan R. “Levodopa phobia”: A new iatrogenic cause of disability in Parkinson disease. Neurology 2005; 64: 923–24.
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 randomised trial. The Lancet - 11 June 2014 DOI: 10.1016/S0140-6736(14)60683-8.
To read more books and articles by Michael S. Okun MD check Twitter @MichaelOkun and these websites with blogs and information on his books and http://parkinsonsecrets.com/ #EndingPD and https://www.tourettetreatment.com/
