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February 11, 2003
Letter to the Editor

Initial agonist treatment of Parkinson disease
A critique

February 11, 2003 issue
60 (3) 390-394

Abstract

The evidence supporting initial dopamine agonist treatment of PD is reviewed. The two rationales for initial agonist treatment are reduced frequency of motor complications and possible relative neuroprotection by dopamine agonists. The basic science supporting these rationales is equivocal. The clinical evidence for advantages of initial agonist treatment is incomplete. More data are required to determine the optimal initial treatment for PD.

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Letters to the Editor
19 June 2003
Reply to Letter to the Editor
Roger L Albin
Kirk A Frey

Dr. Montgomery raises interesting points. We do not discount the results of the DA - LD comparator trials. These trials formed primary data for our analysis. Dr. Montgomery suggests that differences in intensity of treatment measured by the UPDRS motor scale could be an artifact. He suggests that lack of significant differences in the UPDRS activities of daily living scale (ADL) implies equivalent therapeutic effects. Actually, in the CALM-PD trial, there were significant differences favoring LD treatment in the UPDRS ADL scale. [1] The PD Research Group of the United Kingdom (PDRGUK) study comparing initial bromocriptine with LD therapy supports our interpretation. [2] This trial used a different disability assessment method and demonstrated a difference in favor of LD. Dr. Montgomery's point that the motor component of the UPDRS is driven by effects in limited domains is irrelevant. As long as those domains reflect clinically significant phenomena, the motor scale is useful. His power calculations are irrelevant also. If anything, they show that these studies would be relatively insensitive to detecting differences in treatment intensity, which may have biased study outcomes towards a result favoring initial DA treatment.

Dr. Montgomery's differentiation of "acute and reversible" versus "irreversible" side effects is not useful. Dyskinesias are no more or less reversible than hallucinations and so-called acute side effects are often more disabling than dyskinesias. Dr. Montgomery's suggestion that dyskinesias are qualitatively different from other side-effects ignores that fact that many PD subjects experience mild and insignificant dyskinesias. In the PDRGUK study, which has unparalleled follow-up, there was no difference in the incidence of moderate to severe dyskinesias. [2]

Dr. Montgomery errs in implying that we are extreme skeptics. Authentic extreme skepticism is an epistemological stance precluding conclusions about any feature of human experience. [3] We are mitigated skeptics; reaching conclusions only after critical evaluation of data. [3]

Finally, debate about initial treatment of PD is appropriate and necessary. Patients do not have unlimited rights to decide how they are treated. The generally accepted formulation of medical ethics identifies four crucial principles: respect for autonomy, nonmaleficence, beneficence, and concern for justice. [4] Application of the last three principles involves paternalistic behavior. Dr. Montgomery's remark, which we doubt reflects his actual practice, implies priority for respect for autonomy. Beauchamp and Childress, however, specify that none of the basic principles have priority. [4] Assigning priority to autonomy is questionable philosophy and poor clinical practice.

References:

1. Albin RL, Frey KA. Initial agonist treatments of Parkinson disease: a critique. Neurology 2003;60:390-394.

2. Lees AJ, Katzenschlager R, Head J, et al. Ten-year follow-up of three different initial treatments in de-novo PD. A randomized trial. Neurology 2001;57:1687-1684.

3. Hume D. An enquiry concerning human understanding (Oxford Philosophical Texts) Oxford: Oxford University Press, 1999.

4. Beauchamp TL, Childress JF. Principles of Biomedical Ethics, 5th ed. Oxford: Oxford University Press, 2001.

19 June 2003
Initial agonist treatment of Parkinson disease: A critique
Erwin B Montgomery

The well-considered editorial [1] and two reviews [2, 3] on therapeutic decisions in Parkinson's disease missed several points and some rationales are suspect.

Trials of pramapexole [4] and ropinirole [5] versus levodopa were discounted. The greater dyskinesias with levodopa were attributed to more aggressive treatment interpreted from differences on the Unified Parkinson Disease Rating Scale (UPDRS) motor scores. However, physicians were blinded and could not have utilized different criteria for adequate control. This is supported by the lack of significant difference in the UPDRS activities of daily living (ADL) scores. It is possible that the differences in the UPDRS motor scores were an artifact. Factor analysis demonstrated that certain symptom domains may have a disparate effect on the scores of the UPDRS motor scores [6]. Thus, a slight and perhaps clinically insignificant advantage of levodopa among these symptoms could skew the motor score.

Were differences in UPDRS motor scores sufficient to explain the differences in dyskineisa? From the published data [5], 174 patients would have to be treated have a 90% chance of detecting a significant difference at the p < 0.05 level (Stata, Stata Corporation, College Station, Texas USA). Conversely, only 80 patients would have to be treated to see a significant difference in the prevalence of dyskinesias. Before the introduction of levodopa, only 49 patients would have to be treated.

The higher risks of short-term and lower efficacy of dopamine agonists were used as a "straw-man arguments". The reversible acute side effects are qualitatively different than potentially irreversible dyskinesias. For patients achieving adequate control on either medication, the dopamine agonists are just as efficacious as levodopa. Also, discounting the consequences of dyskinesia skews risk/benefits considerations.

While not intentional, the lack of "smoking gun" evidence may give some the impression of immunity for any position. Alternative explanations are inexhaustible, thus providing limitless ammunition for radical skepticism resulting in therapeutic nihilism. Physicians are not expected to have all the answers but they are expected to use their best judgment. While future research may change the available evidence, the needs of patients today compel the physician to make judgments today.

Finally, if it is the patients or the patients' proxy right to decide how they are treated, then our responsibilities are to present all sides as reasonably. If so, the debate as to whether a physician should prescribe dopamine agonists or levodopa is misdirected.

References:

1. Wooten GF. Agonists vs levodopa in PD: the thrilla of whitha. Neurology 2003;60:360-362.

2. Ahlskog JE. Slowing Parkinson's disease progression: recent dopamine agonist trials Neurology 2003;60:381-389.

3. Albin RL, Frey KA. Initial agonist treatments of Parkinson disease: a critique. Neurology 2003;60:390-394.

4. Parkinson Study Group. Pramipexole vs. levodopa as initial treatment Parkinson disease: a randomized controlled trial. JAMA 2000;284: 1931-1938. 131-1938.

5. Rascol 0, Brooks D, Korczyn A, et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. N Engl J Med 2000;342:1484-1491.

6. Stebbins GT, Goetz CG. Factor structure of the Unified Parkinson's Disease Rating Scale: motor examination. Move Disord 1998;13:633-636.

Information & Authors

Information

Published In

Neurology®
Volume 60Number 3February 11, 2003
Pages: 390-394
PubMed: 12580185

Publication History

Received: May 22, 2002
Accepted: December 2, 2002
Published online: February 11, 2003
Published in print: February 11, 2003

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Authors

Affiliations & Disclosures

Roger L. Albin, MD
From the Departments of Neurology (Drs. Albin and Frey) and Radiology (Nuclear Medicine) (Dr. Frey); and Geriatric Research, Education, and Clinical Center (Dr. Albin), Ann Arbor VAMC, University of Michigan, Ann Arbor.
Kirk A. Frey, MD PhD
From the Departments of Neurology (Drs. Albin and Frey) and Radiology (Nuclear Medicine) (Dr. Frey); and Geriatric Research, Education, and Clinical Center (Dr. Albin), Ann Arbor VAMC, University of Michigan, Ann Arbor.

Notes

Address correspondence and reprint requests to Dr. Roger L. Albin, 4412D, Kresge III Building, 200 Zina Pitcher Place, Ann Arbor, MI, 48109-0585; e-mail: [email protected]

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