Neurology -- Correspondence for Ahlskog, 60 (3) 381-389

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Correspondence published:

Reply to Letter to the Editor: J Eric Ahlskog (19 June 2003)

Slowing Parkinson’s disease progression: Recent dopamine agonist trialsRevised Letter to the Editor: Erwin B Montgomery (19 June 2003)

Reply to Letter to the Editor 19 June 2003

J Eric Ahlskog
Mayo Clinic Rochester MN
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Re: Reply to Letter to the Editor

eahlskog{at}mayo.edu J Eric Ahlskog

Dr. Montgomery has raised the very interesting point regarding the pramipexole (4) and ropinirole (5) clinical trials: levodopa monotherapy was significantly more efficacious, despite liberal supplemental levodopa in the dopamine agonist arms. In fact, better efficacy with levodopa monotherapy was also found in two other dopamine agonist multi-center trials. [1, 2] These results should not be an artifact of the UPDRS motor test battery since ADL scores tended to follow this same pattern. UPDRS- ADL scores were superior in the levodopa arms in all three trials where reported. This was highly significant (p=0.001) in one (4), with a similar, albeit non-significant trend (p=0.08) in another (5); in the third study, the ADL scores were better in the levodopa arm but no statistical analyses were reported. [1]
How to explain this? Despite the double-blind study designs, it is conceivable that treating physicians were able to sense the true identity of the study drugs from the patients' responses. If biased toward agonist therapy, they might have tended to limit the levodopa dosage in the dopamine agonist arms (resulting in fewer dyskinesias). However, it seems unlikely that investigators in all four trials would display such consistent bias.
I suggested an alternative explanation (2): these findings are what one would predict if dopamine transporter (DAT) was up regulated by dopamine agonist therapy. Greater expression of DAT per neuron should result in more effective clearance of dopamine from the synaptic region. This should result in fewer dyskinesias but a less robust anti- parkinsonian response, which were the findings in all four clinical trials (4,5). [1, 2] Similar regulatory changes in other proteins involved in dopamine transport, metabolism and neurotransmission could also generate this outcome.
The phrase, "…potentially irreversible dyskinesias…" deserves comment. Dyskinesias represent a "short-duration" response to a given levodopa dose. They resolve within a few hours and will totally abate with levodopa dose reduction; hence, not truly irreversible. The dyskinesia potential is related to the duration of PD and not simply to the duration of levodopa treatment. [3, 4] Dyskinesias are rare early in treatment but with approximately 40% incidence by five years. [4] Among some of those affected, the dyskinesias will be limited and inconsequential. For others, the dyskinesias will be controlled by medication adjustments. Only a small minority of our patients displays the worst-case scenario that the term, "dyskinesias" brings to mind: wild, generalized flailing chorea that only resolves with levodopa reduction to subtherapeutic levels. Perhaps dyskinesias should not be the primary factor in our early PD treatment decisions.
Finally, dopamine agonist monotherapy is not nearly as "efficacious" as levodopa. This is the reason that only a very limited number of patients could be maintained on agonist monotherapy for more than a few years in any of the published clinical trials to date.
References:
1. Rinne UK, Bracco F, Chouza C, et al. Early treatment of Parkinson's disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial. Drugs 1998; 55:23-30.
2. Whone AL, Remy P, Davis MR, et al. The REAL-PET study: slower progression in early Parkinson's disease treated with ropinirole compared with l-dopa. Neurology 2002; 58:A82-A83.
3. Muenter MD, Ahlskog JE. Dopa dyskinesias and fluctuations are not related to dopa treatment duration. Ann. Neurol. 2000; 48:464.
4. Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Movement Disorders 2001; 16:448-458.

Slowing Parkinson’s disease progression: Recent dopamine agonist trialsRevised Letter to the Editor 19 June 2003

Erwin B Montgomery
Cleveland Clinic Foundation OH
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Re: Slowing Parkinson’s disease progression: Recent dopamine agonist trialsRevised Letter to the Editor

montgoe{at}cesmtp.ccf.org 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.