ARTICLE IN BRIEF
A new paper finding that levodopa is not neurotoxic has elicited debate among Parkinson disease experts.
THE CUMULATIVE DOSE ...Image Tools
Whether or not the research reported in the Sept. 14 online issue of Neurology will put to rest lingering fears that levodopa, the most effective treatment for Parkinson disease (PD), damages dopamine-producing cells, depends on who you talk to. In accompanying editorials, Peter A. Lewitt, MD, and co-authors write the data in the new study provide unequivocal proof that fears about toxicity are unfounded, while C. Warren Olanow, MD, and Jose A. Obeso, MD, say the findings leave still more questions unanswered. [See “Yes, No or Maybe? Is Levodopa Toxic?”] And independent experts expressed similar ambivalence in interviews with Neurology Today.
In the current study, the researchers hypothesized that if levodopa was toxic, then greater drug exposure would result in more neuronal loss and increased presence of Lewy bodies, the pathological signature of the disease. They measured the density of pigmented neurons in the substantia nigra (SN) and the number of Lewy bodies in autopsy samples from 96 PD patients — and found no correlation with length of levodopa use and disease progression. Because it is difficult to distinguish the effects of the drug from the long-term effects of the disease, the authors also conducted a sub-group analysis of 40 younger patients, ages 40-65. They also failed to find a correlation between levodopa use and either neuronal loss or the presence of Lewy bodies, thereby supporting their conclusion that levodopa “does not enhance progression of PD pathology.”
Among data, they reported that the mean lifetime dose of levodopa correlated significantly with PD duration in the 96 patients (p<0.001) but in 40 younger PD patients who had longer disease duration, there was no significant correlation between levodopa and total SN neuronal density (p=0.07). There was also no difference in levodopa dose between Braak PD stages (p=0.58) and, in the younger subgroup, there was no relationship of levodopa dose to either cortical (p=0.47) or nigral (p=0.48) Lewy bodies density.
“In science there's never a final answer, but this paper puts to rest the notion that levodopa kills nigral cells,” said corresponding author, Andrew J. Lees, MD, director of the Reta Lila Weston Institute of Neurological Studies at University College London, and director of the Queen Square Brain Bank for Neurological Disorders, which provided the samples analyzed. “That doesn't mean levodopa doesn't have some permanent effects on the brain, but I think our paper provides strong evidence that you're not killing dopamine-containing cells. I hope this work will stop patients from being frightened to take levodopa.”
ANY LINGERING DOUBTS?
“The important finding of the study is that the cumulative dose of levodopa did not add to substantia nigra toxicity,” said William J. Weiner, MD, who has authored several papers challenging the notion that the drug somehow harms the brain. “This paper adds neuropathologic confirmation to what most neurologists have finally started to accept, which is that levodopa is not toxic and is an extremely helpful drug. I hope that this is the final, final nail in the coffin of the idea of levodopa toxicity.” Dr. Weiner serves on the editorial advisory board of Neurology Today, is chair of the department of neurology at the University of Maryland School of Medicine, and director of the Maryland Parkinson's Disease and Movement Disorders Center.
“I don't believe levodopa is toxic, but it clearly changes the way the brain reacts,” said John Nutt, MD, co-founder and director of the Oregon Health Sciences University Parkinson Center of Oregon and Movement Disorders Program, and co-director of the Portland VA Medical Center Parkinson's Disease Research, Education and Clinical Center.
“Whether the dyskinesias, hallucinations and other symptoms are induced by the drug or the disease is unclear, but this paper suggests that levodopa does not hasten the disease process. I'm not sure levodopa prolongs life, but it certainly provides more functional ability, and this paper certainly provides more evidence against those who avoid early treatment with levodopa because they believe it might be toxic.”
Besides, side-effects of levodopa can be managed by reducing the dose of levodopa — or spreading it out over two or more doses, said Mark Stacy, MD, lead author of a 2008 paper on the subject in the journal, Clinical Neuropharmacology. Still, he sometimes postpones administering levodopa.
“I do not think levodopa is harmful to people with PD, but it is tightly linked to dyskinesias, and when appropriate I might try to delay the start of levodopa to avoid this,” he said. “It is difficult enough for a patient to deal with the reality of having a neurodegenerative disease. If I start levodopa, patients who develop dyskinesias a year later have every right to fear that their brain is melting away. Then they read that levodopa is bad, and they suffer even further.”
But, according to another PD expert, the paper, while certain to have far-reaching effects, should be interpreted cautiously. “First, the major limitation is that the findings are based on retrospective data about the cumulative and maximum dose of L-dopa and an analysis of only a subset of 40 patients with relatively young-onset PD (40-65 years of age),” said Joseph Jankovic, MD, Distinguished Chair in Movement Disorders and director of the Parkinson's Disease Center and Movement Disorders Clinic at Baylor College of Medicine in Houston, who was not involved with the studies.
“Second, the ventral tier of substantia nigra did show a significantly decreased neuronal density with increasing lifetime cumulative dose of L-dopa. Third, the three patients exposed to high dosages of L-dopa did have a lower mean substantia nigra density of pigmented neurons than the entire population, even though, possibly because of a small sample size, this difference did not reach statistical significance. Nevertheless, despite these limitations, the authors should be congratulated on taking full advantage of the Queen Square Brain bank to answer not only this important question about L-dopa toxicity, but many other questions that can be best addressed by a careful clinical-pathologic correlative study.”
THEORY ON TOXICITY
The belief that levodopa might be toxic emerged from early in vitro research that found the drug generated free radicals, hydrogen peroxide, and quinones — highly reactive molecules capable of attacking neurons and promoting Parkinson disease. However, these studies used high concentrations of levodopa on neurons that were not cultured with glia, which provide antioxidant protection. Later research in which neurons were surrounded by glial cells eliminated the adverse effects of levodopa.
Nevertheless, drug companies that had developed dopamine agonists, an alternative or adjunct to levodopa, seized on this research to promote the notion that levodopa damaged the brain, according to Dr. Weiner. “The whole concept of levodopa toxicity was driven by pharmaceutical interests when dopamine agonists were introduced,” Dr. Weiner said. “They manufactured dopamine agonists and had a vested interest in making people nervous about levodopa toxicity. The strange thing is this concept of levodopa toxicity began to gain steam after we had been using levodopa for 25 years. There was no evidence from clinical experience that levodopa harmed patients, but these companies were extremely effective in swaying opinion among movement disorders specialists and patients.”
As a result, some PD patients, influenced by their own research or by their physicians, refused to take levodopa. “You used to see patients all the time with early to moderate PD who were almost ready to be in a wheelchair because they were afraid to take levodopa,” Dr. Weiner said. “It was terrible to see that because everyone agrees that levodopa is the best treatment for relieving motor symptoms of PD. Almost every PD patient, given the choice between being slower and stiffer, or taking levodopa and developing some dyskinesias, would prefer the dyskinesias. At least then they can get up, move around, do what they want to do.”
IS LEVODOPA NEUROPROTECTIVE?
In mammals, the enzyme aromatic-L-amino-acid decarboxylase, or dopa decarboxylase, converts levodopa to dopamine. Since levodopa, unlike dopamine, can cross the blood-brain barrier, it can boost levels of dopamine in people deficient in this neurotransmitter. Originally published in 2004 in The New England Journal of Medicine, The ELLDOPA study (Earlier versus Later LevoDOPA), which set out to determine if levodopa was toxic, even suggested that levodopa might be neuroprotective.
In a 2005 report on the study in the Journal of Neurology, Stanley Fahn, MD, H. Houston Merritt Professor of Neurology at the Columbia University Medical Center and leader of the Parkinson Study Group that conducted the research, said that the clinical outcomes “support the concept that the drug does not hasten the disease progression, but rather may slow down the rate of the disease.” However, he also noted that the beta-CIT SPECT sub-study, produced contradictory evidence suggesting that “levodopa causes a more rapid decline in the integrity of the dopamine transporter located in the nigrostriatal nerve terminals in the striatum” — a finding that fueled concern about the drug's potential toxicity.
A subsequent survey showed that most clinicians did not believe levodopa was neuroprotective, and many remained concerned that the drug might induce motor complications. “Thus, the ELLDOPA study failed to change the treating pattern of PD, and the clinicians require more convincing evidence of either neuroprotection or neurotoxicity of levodopa before they would alter their treatment approach,” Dr. Fahn concluded in a 2006 review of the ELLDOPA study published in the journal, Parkinson's Disease and Related Disorders.
YES, NO OR MAYBE? IS LEVODOPA TOXIC?
DR. C. WARREN OLANOW...Image Tools
DR. PETER A. LEWITT ...Image Tools
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Olanow CW, Obeso JA. Levodopa toxicity and Parkinson disease: Still a need for equipoise. Neurology 2011; E-pub 2011 Sept. 14.
LeWitt PA, Dubo J, Singer C. Is levodopa toxic?: Insights from a brain bank. Neurology 2011; E-pub 2011 Sept. 14.
Fahn S, Oakes D, Marek K et al, for the Parkinson Study Group. Levodopa and the progression of Parkinson's disease. N Engl J Med 2004; 351:2498-2508.
Weiner WJ. Is levodopa toxic? Arch Neurol
Fahn S, et al, for the Parkinson Study Group. Does levodopa slow or hasten the rate of progression of Parkinson's disease? J Neurol 2005;252 Suppl, IV37-IV42.
Fahn S. A new look at levodopa based on the ELLDOPA study. Parkinson's Dis Relat Disord 2006;70(9):419-426.
Stacy M and Galbreath A. Optimizing long-term therapy for Parkinson disease: Options for treatment-associated dyskinesia. Clini Neuropharmacol 2008;31(1):51-56.