FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 351:2498-2508 December 9, 2004 Number 24 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Editorial by Press, D. Z. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Despite the known benefit of levodopa in reducing the symptoms of Parkinson's disease, concern has been expressed that its use might hasten neurodegeneration. This study assessed the effect of levodopa on the rate of progression of Parkinson's disease.

Methods In this randomized, double-blind, placebo-controlled trial, we evaluated 361 patients with early Parkinson's disease who were assigned to receive carbidopa–levodopa at a daily dose of 37.5 and 150 mg, 75 and 300 mg, or 150 and 600 mg, respectively, or a matching placebo for a period of 40 weeks, and then to undergo withdrawal of treatment for 2 weeks. The primary outcome was a change in scores on the Unified Parkinson's Disease Rating Scale (UPDRS) between baseline and 42 weeks. Neuroimaging studies of 142 subjects were performed at baseline and at week 40 to assess striatal dopamine-transporter density with the use of iodine-123–labeled 2--carboxymethoxy-3--(4-iodophenyl)tropane ([¹²³I]-CIT) uptake.

Results The severity of parkinsonism increased more in the placebo group than in all the groups receiving levodopa: the mean difference between the total score on the UPDRS at baseline and at 42 weeks was 7.8 units in the placebo group, 1.9 units in the group receiving levodopa at a dose of 150 mg daily, 1.9 in those receiving 300 mg daily, and –1.4 in those receiving 600 mg daily (P<0.001). In contrast, in a substudy of 116 patients the mean percent decline in the [¹²³I]-CIT uptake was significantly greater with levodopa than placebo (–6 percent among those receiving levodopa at 150 mg daily, –4 percent in those receiving it at 300 mg daily, and –7.2 percent among those receiving it at 600 mg daily, as compared with –1.4 percent among those receiving placebo; 19 patients with no dopaminergic deficits on the baseline scans were excluded from the analysis) (P=0.036). The subjects receiving the highest dose of levodopa had significantly more dyskinesia, hypertonia, infection, headache, and nausea than those receiving placebo.

Conclusions The clinical data suggest that levodopa either slows the progression of Parkinson's disease or has a prolonged effect on the symptoms of the disease. In contrast, the neuroimaging data suggest either that levodopa accelerates the loss of nigrostriatal dopamine nerve terminals or that its pharmacologic effects modify the dopamine transporter. The potential long-term effects of levodopa on Parkinson's disease remain uncertain.

Source Information

The writing committee of the Earlier versus Later Levodopa study (Stanley Fahn, M.D., Columbia University, New York; David Oakes, Ph.D., Ira Shoulson, M.D., Karl Kieburtz, M.D., and Alice Rudolph, Ph.D., University of Rochester, Rochester, N.Y.; Anthony Lang, M.D., Toronto Western Hospital, Toronto; C. Warren Olanow, M.D., Mount Sinai School of Medicine, New York; Caroline Tanner, M.D., Ph.D., the Parkinson's Institute, Sunnyvale, Calif.; and Kenneth Marek, M.D., Institute for Neurodegenerative Disorders, New Haven, Conn.) takes responsibility for the content of this article.

Address reprint requests to Dr. Stanley Fahn at the Neurological Institute, 710 W. 168th St., New York, NY 10032-3784, or at fahn{at}neuro.columbia.edu.

Full Text of this Article

Related Letters:

Levodopa and the Progression of Parkinson's Disease
Walton-Hadlock J. L., Fahn S., Keiburtz K., Tanner C. M., the Parkinson Study Group
Extract | Full Text | PDF  
N Engl J Med 2005; 352:1386, Mar 31, 2005. Correspondence

This article has been cited by other articles:

• Uc, E. Y., McDermott, M. P., Marder, K. S., Anderson, S. W., Litvan, I., Como, P. G., Auinger, P., Chou, K. L., Growdon, J. C., On behalf of the Parkinson Study Group DATATOP Inv, (2009). Incidence of and risk factors for cognitive impairment in an early Parkinson disease clinical trial cohort. Neurology 73: 1469-1477 [Abstract] [Full Text]  
• Jarraya, B., Boulet, S., Scott Ralph, G., Jan, C., Bonvento, G., Azzouz, M., Miskin, J. E., Shin, M., Delzescaux, T., Drouot, X., Herard, A.-S., Day, D. M., Brouillet, E., Kingsman, S. M., Hantraye, P., Mitrophanous, K. A., Mazarakis, N. D., Palfi, S. (2009). Dopamine Gene Therapy for Parkinson's Disease in a Nonhuman Primate Without Associated Dyskinesia. Sci Transl Med 1: 2ra4-2ra4 [Abstract] [Full Text]  
• Silveira-Moriyama, L, Schwingenschuh, P, O'Donnell, A, Schneider, S A, Mir, P, Carrillo, F, Terranova, C, Petrie, A, Grosset, D G, Quinn, N P, Bhatia, K P, Lees, A J (2009). Olfaction in patients with suspected parkinsonism and scans without evidence of dopaminergic deficit (SWEDDs). J. Neurol. Neurosurg. Psychiatry 80: 744-748 [Abstract] [Full Text]  
• Jokinen, P., Helenius, H., Rauhala, E., Bruck, A., Eskola, O., Rinne, J. O. (2009). Simple Ratio Analysis of 18F-Fluorodopa Uptake in Striatal Subregions Separates Patients with Early Parkinson Disease from Healthy Controls. JNM 50: 893-899 [Abstract] [Full Text]  
• Olanow, C. W., Stern, M. B., Sethi, K. (2009). The scientific and clinical basis for the treatment of Parkinson disease (2009). Neurology 72: S1-S136 [Abstract] [Full Text]  
• Nilsson, A., Falth, M., Zhang, X., Kultima, K., Skold, K., Svenningsson, P., Andren, P. E. (2009). Striatal Alterations of Secretogranin-1, Somatostatin, Prodynorphin, and Cholecystokinin Peptides in an Experimental Mouse Model of Parkinson Disease. Mol. Cell. Proteomics 8: 1094-1104 [Abstract] [Full Text]  
• Pisani, A., Shen, J. (2009). Levodopa-induced dyskinesia and striatal signaling pathways. Proc. Natl. Acad. Sci. USA 106: 2973-2974 [Full Text]  
• Sujith, O.K., Lane, C. (2009). Review: Therapeutic options for continuous dopaminergic stimulation in Parkinson's disease. Therapeutic Advances in Neurological Disorders 2: 105-113 [Abstract]  
• Tolosa, E., Gaig, C., Santamaria, J., Compta, Y. (2009). Diagnosis and the premotor phase of Parkinson disease. Neurology 72: S12-S20 [Abstract] [Full Text]  
• Brotchie, J., Fitzer-Attas, C. (2009). Mechanisms compensating for dopamine loss in early Parkinson disease. Neurology 72: S32-S38 [Abstract] [Full Text]  
• Lang, A. E. (2009). When and how should treatment be started in Parkinson disease?. Neurology 72: S39-S43 [Abstract] [Full Text]  
• Schapira, A. H.V. (2009). Molecular and clinical pathways to neuroprotection of dopaminergic drugs in Parkinson disease. Neurology 72: S44-S50 [Abstract] [Full Text]  
• Rascol, O. (2009). "Disease-modification" trials in Parkinson disease: Target populations, endpoints and study design. Neurology 72: S51-S58 [Abstract] [Full Text]  
• Olanow, C. W. (2009). Can we achieve neuroprotection with currently available anti-parkinsonian interventions?. Neurology 72: S59-S64 [Abstract] [Full Text]  
• LeWitt, P. A. (2008). Levodopa for the Treatment of Parkinson's Disease. NEJM 359: 2468-2476 [Full Text]  
• Tarsy, D., Simon, D. K., Eric Ahlskog, J. (2008). BEATING A DEAD HORSE: DOPAMINE AND PARKINSON DISEASE. Neurology 71: 1651-1652 [Full Text]  
• Schifitto, G., Friedman, J. H., Oakes, D., Shulman, L., Comella, C. L., Marek, K., Fahn, S., The Parkinson Study Group ELLDOPA Investigators, (2008). Fatigue in levodopa-naive subjects with Parkinson disease. Neurology 71: 481-485 [Abstract] [Full Text]  
• Davie, C. A. (2008). A review of Parkinson's disease. Br Med Bull 86: 109-127 [Abstract] [Full Text]  
• Marras, C., Lang, A. (2008). Invited Article: Changing concepts in Parkinson disease: Moving beyond the Decade of the Brain. Neurology 70: 1996-2003 [Abstract] [Full Text]  
• Zhang, X., Andren, P. E., Greengard, P., Svenningsson, P. (2008). Evidence for a role of the 5-HT1B receptor and its adaptor protein, p11, in L-DOPA treatment of an animal model of Parkinsonism. Proc. Natl. Acad. Sci. USA 105: 2163-2168 [Abstract] [Full Text]  
• Ahlskog, J. E. (2007). Beating a dead horse: Dopamine and Parkinson disease. Neurology 69: 1701-1711 [Abstract] [Full Text]  
• Schapira, A. H. V. (2007). Treatment Options in the Modern Management of Parkinson Disease. Arch Neurol 64: 1083-1088 [Full Text]  
• Huang, C., Tang, C., Feigin, A., Lesser, M., Ma, Y., Pourfar, M., Dhawan, V., Eidelberg, D. (2007). Changes in network activity with the progression of Parkinson's disease. Brain 130: 1834-1846 [Abstract] [Full Text]  
• Mallet, L., Schupbach, M., N'Diaye, K., Remy, P., Bardinet, E., Czernecki, V., Welter, M.-L., Pelissolo, A., Ruberg, M., Agid, Y., Yelnik, J. (2007). Stimulation of subterritories of the subthalamic nucleus reveals its role in the integration of the emotional and motor aspects of behavior. Proc. Natl. Acad. Sci. USA 104: 10661-10666 [Abstract] [Full Text]  
• Chou, K. L., Stacy, M. A. (2007). Skin rash associated with Sinemet does not equal levodopa allergy. Neurology 68: 1078-1079 [Full Text]  
• Xiao, D., Bastia, E., Xu, Y.-H., Benn, C. L., Cha, J.-H. J., Peterson, T. S., Chen, J.-F., Schwarzschild, M. A. (2006). Forebrain Adenosine A2A Receptors Contribute to L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Hemiparkinsonian Mice. J. Neurosci. 26: 13548-13555 [Abstract] [Full Text]  
• Gaynes, B. I. (2006). Independent patterns of damage within magno-, parvo- and koniocellular pathways in Parkinson's disease (Silva MF et al. Brain 2005; 128: 2260-2271). Brain 129: e61-e61 [Full Text]  
• Wider, C., Russmann, H., Villemure, J.-G., Robert, B., Bogousslavsky, J., Burkhard, P. R., Vingerhoets, F. J. G. (2006). Long-duration response to levodopa in patients with advanced Parkinson disease treated with subthalamic deep brain stimulation.. Arch Neurol 63: 951-955 [Abstract] [Full Text]  
• Nutt, J. G., Deleu, D., Hanssens, Y., Nyholm, D., Jansson, R., Willows, T., Remahl, I. N. (2006). Long-term 24-hour duodenal infusion of levodopa: outcome and dose requirements.. Neurology 66: 1611-1612 [Full Text]  
• Poewe, W. (2006). The need for neuroprotective therapies in Parkinson's disease: A clinical perspective. Neurology 66: S2-S9 [Abstract] [Full Text]  
• Hauser, R. A., Zesiewicz, T. A. (2006). Clinical trials aimed at detecting neuroprotection in Parkinson's disease. Neurology 66: S58-S68 [Abstract] [Full Text]  
• Chen, J. J., Ly, A.-V. (2006). Rasagiline: A second-generation monoamine oxidase type-B inhibitor for the treatment of Parkinson's disease. Am J Health Syst Pharm 63: 915-928 [Abstract] [Full Text]  
• Suchowersky, O., Gronseth, G., Perlmutter, J., Reich, S., Zesiewicz, T., Weiner, W. J. (2006). Practice Parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.. Neurology 66: 976-982 [Abstract] [Full Text]  
• Pahwa, R., Factor, S. A., Lyons, K. E., Ondo, W. G., Gronseth, G., Bronte-Stewart, H., Hallett, M., Miyasaki, J., Stevens, J., Weiner, W. J. (2006). Practice Parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.. Neurology 66: 983-995 [Abstract] [Full Text]  
• Holloway, R. G. Jr., Jozefowicz, R. F. (2006). Update in neurology.. ANN INTERN MED 144: 421-426 [Full Text]  
• The NINDS NET-PD Investigators, (2006). A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology 66: 664-671 [Abstract] [Full Text]  
• Schapira, A H V (2005). Present and future drug treatment for Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 76: 1472-1478 [Abstract] [Full Text]  
• Rodriguez-Oroz, M. C., Obeso, J. A., Lang, A. E., Houeto, J.-L., Pollak, P., Rehncrona, S., Kulisevsky, J., Albanese, A., Volkmann, J., Hariz, M. I., Quinn, N. P., Speelman, J. D., Guridi, J., Zamarbide, I., Gironell, A., Molet, J., Pascual-Sedano, B., Pidoux, B., Bonnet, A. M., Agid, Y., Xie, J., Benabid, A.-L., Lozano, A. M., Saint-Cyr, J., Romito, L., Contarino, M. F., Scerrati, M., Fraix, V., Van Blercom, N. (2005). Bilateral deep brain stimulation in Parkinson's disease: a multicentre study with 4 years follow-up. Brain 128: 2240-2249 [Abstract] [Full Text]  
• Nutt, J. G., Wooten, G. F. (2005). Diagnosis and Initial Management of Parkinson's Disease. NEJM 353: 1021-1027 [Full Text]  
• Chen, J. J., Swope, D. M. (2005). Clinical Pharmacology of Rasagiline: A Novel, Second-Generation Propargylamine for the Treatment of Parkinson Disease. J Clin Pharmacol 45: 878-894 [Abstract] [Full Text]  
• Walton-Hadlock, J. L., Fahn, S., Keiburtz, K., Tanner, C. M., the Parkinson Study Group, (2005). Levodopa and the Progression of Parkinson's Disease. NEJM 352: 1386-1386 [Full Text]  
• (2005). Does Levodopa Affect Parkinson Disease Progression?. JWatch Neurology 2005: 9-9 [Full Text]  
• Jankovic, J. (2005). Progression of Parkinson Disease: Are We Making Progress in Charting the Course?. Arch Neurol 62: 351-352 [Full Text]  
• (2005). Does Levodopa Influence Progression of Parkinson Disease?. JWatch Psychiatry 2005: 9-9 [Full Text]  
• (2004). Does Levodopa Influence Progression of Parkinson Disease?. JWatch General 2004: 2-2 [Full Text]  
• Press, D. Z. (2004). Parkinson's Disease Dementia -- A First Step?. NEJM 351: 2547-2549 [Full Text]  
• Suchowersky, O., Gronseth, G., Perlmutter, J., Reich, S., Zesiewicz, T., Weiner, W. J. (2006). Practice Parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.. Neurology 66: 976-982 [Abstract] [Full Text]  
• Pahwa, R., Factor, S. A., Lyons, K. E., Ondo, W. G., Gronseth, G., Bronte-Stewart, H., Hallett, M., Miyasaki, J., Stevens, J., Weiner, W. J. (2006). Practice Parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.. Neurology 66: 983-995 [Abstract] [Full Text]