This report from the  Sixth International Congress of Parkinson's Disease
and Movement Disorders summarizes current research and the continuing
debate on PD meds -- when to start levodopa, which meds to start with,
comparisons between the various dopamine agonists, old and new agonists,
etc. Once again no consensus yet among the experts.  (full report
available on Medscape  at  http://www.medscape.com)
I think the last paragraph may be the most significant part of this
report -- so I moved it to the beginning:

"Perhaps the most relevant comment, sobering as it was, was made by Dr.
Lees at the end of the discussion. He pointed out that when considering
the entire course of PD, which can span several decades, the first 5
years are usually marked by relatively minor symptoms that can be
controlled adequately with either levodopa or an agonist. As he put it,
"the first 5 years are easy" in terms of treatment choices. The much more
difficult period is the following years, during which motor fluctuations,
variation in response to levodopa, and the progression of symptoms
refractory to levodopa take a more serious toll on the quality of life of
patients with PD than in the first 5 years. Thus, without denying the
importance of making the best use of the treatment options that we have
for the initial period, he expressed hope that the search will continue
for better treatments for the more advanced stages of PD."

FROM: Medscape Neurology, 2000
www.medscape.com
Conference Highlights From the Sixth International Congress of
Parkinson's Disease and Movement Disorders

Clinical Trials in PD

Long-term treatment of patients with PD with levodopa is accompanied,
after a few years, by the apparently inevitable development of motor
complications. These mostly consist of the following:
1.      a shortened duration of efficacy (down to as little as 1 to 2 hours),
which leads to "on-off" fluctuations in a patient's motor function; and
2.      dyskinesias, which are continuous involuntary writhing movements of
the face, neck, or limbs.

Whether delaying treatment with levodopa helps to delay or reduce the
severity of these complications remains an unanswered question, leading
to difficult choices for most patients with PD and their physicians. Most
patients would be willing to forgo use of levodopa for a few years if
this postponed the onset of motor complications. On the other hand,
withholding levodopa's sometimes substantial benefit during a period of
greatest activity and productivity would be worthless if the
complications appear independently of the initiation of levodopa
treatment.

Dopamine Receptor Agonists

Three studies compared the effects of using a dopamine receptor agonist,
with or without levodopa, to using levodopa alone. The dopamine agonists
most commonly used for PD are pergolide, pramipexole, and ropinirole. All
3 studies compared the rate of development of motor complications in each
treatment group. The design of an ongoing study, comparing early
treatment with levodopa to placebo treatment, was also described.

Pergolide vs Levodopa

Dr. Wolfgang H. Oertel of Marburg, Germany, reported the results of the
PELMOPET (PErgolide vs Levodopa MOnotherapy with Positron Emission
Tomography [PET] scan) trial.[11] The participants were 44 patients in
the early stages of PD (Hoehn and Yahr stage 1 to 2) with a demonstrated
response to dopamine receptor stimulation (positive apomorphine test
result), who had not previously been treated with levodopa for more than
2 weeks. They were randomized to be treated with either pergolide alone
or levodopa alone for at least 3 years. After 1 year of treatment,
patients receiving pergolide had significantly fewer and less severe
motor complications than the patients receiving levodopa. However, after
3 years this difference disappeared. Moreover, the improvement in motor
function provided by the drug was always greater for patients taking
levodopa.
The researchers also obtained fluorodopa PET scans of study patients'
brains. Uptake of fluorodopa by the striatum is a measure of PD
progression, decreased uptake correlating with advancing disease. There
was no significant difference in the decrease in fluorodopa uptake
between the 2 groups of patients. These results suggest that
1.      using an agonist instead of levodopa delays the onset of severe motor
complications;
2.      in the long run these complications develop anyway;
3.      levodopa may provide better symptom control;
4.      there is no difference in disease progression between the 2
treatments.

Pramipexole vs Levodopa

Dr. Ira Shoulson of the University of Rochester, New York, reported the
initial results of the CALM-PD (Comparison of the Agonist pramipexole vs
Levodopa on Motor complications in PD) study.[12] A total of 301 patients
with mild-to-moderate PD, not recently treated with levodopa, were
randomized to blind treatment with either the dopamine receptor agonist
pramipexole or levodopa.
Unlike the previous study, treating physicians were allowed to supplement
the blinded treatment with open-label levodopa if they deemed necessary;
a similar proportion of patients in each group ended up receiving this
supplementation. After 2 years of treatment, fewer patients in the
pramipexole group developed motor complications compared with patients in
the levodopa group. The levodopa group derived better motor benefit. A
brain imaging scan at the beginning and end of the study showed no
difference in disease progression between the 2 groups (the technique
used was "beta-CIT" single photon emission computed tomography (SPECT)
scan, an imaging technique measuring the amount of remaining dopamine
transporter- also a marker of PD severity).
This study showed after 2 years results similar to the PELMOPET study at
1 year: fewer patients developed motor complications when the initial
treatment is with an agonist rather than levodopa. Remarkably, symptom
control was still better in the levodopa group, even though supplemental
levodopa was used in both groups to optimize treatment. This result
raises several questions about treatment decisions but cannot be
explained at present. As for the long-term effects of the 2 treatments,
clues may come from a controlled extension of this study currently under
way.

Ropinirole vs Levodopa
Dr. Oliver Rascol of the University Hospital in Toulouse, France,
described various findings of a study comparing ropinirole to levodopa
(O56 study).[13] A total of 268 patients were randomized to take
ropinirole or levodopa. The use of supplemental levodopa in either group
was permitted to maximize symptomatic benefit. Patients were followed up
for 5 years. The incidence of dyskinesia after 5 years was significantly
less in the ropinirole group compared with the levodopa group (20% vs
46%). As for effectiveness in symptom control, Dr. Rascol emphasized that
the activities of daily living scores remained similar in the 2 groups.
This may explain why the motor benefit from the dopamine agonist was less
than from levodopa in the PELMOPET and CALM-PD studies, even though
supplemental levodopa could be given to both groups of patients in these
studies. If the improvement perceived by the patient (as reflected in the
activities of daily living score) was the same, then the difference in
motor benefit scores may not be clinically significant.
Another important finding in this study was that the rate of development
of dyskinesia was nearly 0 while the patients were taking ropinirole
alone.  Most motor complications developed after supplementary levodopa
was added to the therapy. In addition, the progression of the dyskinesias
after the addition of levodopa was not faster than for the patients
taking levodopa alone. Thus, the benefit of using ropinirole as initial
treatment is maintained even after dyskinesias develop.

Earlier vs Later Levodopa
Intertwined with the question of whether early PD treatment should be
with an agonist or levodopa is another old but as yet unanswered
question- whether delaying the start of treatment with levodopa has any
influence on the development of motor fluctuations or on the course of
the disease itself. Dr. Stanley Fahn of Columbia University in New York,
NY, outlined the design of the ELLDOPA (Earlier vs Later Levodopa
therapy) study, an ongoing study addressing the latter question.[14]
A total of 360 patients in the early stages of PD are being randomized to
receive levodopa therapy or placebo for 9 months. After this period they
will be reexamined, and the change in severity of parkinsonism from
before entering the study will be compared in the 2 groups. If levodopa,
as has been widely thought, indeed provides only relief of symptoms and
does not affect the course of PD, then the change in examination should
be the same in both groups. Moreover, in a smaller group of patients the
amount of neurodegeneration that takes place during the 9 months of the
study will be assessed by comparing beta-CIT PET scans before and after
treatment in each group.

Medical Therapies in PD

New vs Old Dopamine Agonists

This session consisted of point-counterpoint style presentations on each
side of 2 major current debates in this field. One subject was whether
the new dopamine agonists (ropinirole, pramipexole, and cabergoline) are
better than older ones (bromocriptine and pergolide). Dr. Donald B. Calne
of the University of British Columbia in Vancouver, Canada, presented the
arguments for the positive answer.[15] One of the main arguments is that
the new agonists are at least designed to be more selective than the
older ones in their action on dopamine receptors. Such selectivity often
implies higher efficacy and lower frequency and range of adverse effects.
Whether these advantages are real and clinically significant,
unfortunately, has not been demonstrated, since there have been no direct
comparisons of efficacy and adverse effect profiles between the new and
the old agonists.
Dr. Anthony E. Lang of the Toronto Western Hospital in Toronto, Canada,
argued that the new dopamine agonists are not better than the old
ones.[16] He focused on what "better" really means in this context. He
argued that it is not yet clear whether efficacy, ease of use, or adverse
effect profile are any better for the new agonists. He also pointed out
that the new drugs are much more expensive than the old ones, and this
should be included in the assessment of which drug should be used-at
least until definitive studies establish a medical advantage for one drug
over another.

What Should Be the Initial Drug?

Immediately following the discussion of new vs old dopamine agonists was
a debate on whether treatment of PD should begin with agonists or
levodopa.  On this issue, Dr. S. Gimenez-Roldan of the Hospital General
Universitario Gregorio Maranon, Madrid, Spain argued in favor of starting
with agonists.[17] One argument for this position can now be considered
evidence based: 3 studies described in the previous session found 3
agonists to delay the onset of motor complications associated with
levodopa therapy.
Another argument has been suggested by theories and laboratory evidence
on the mechanisms of neurodegeneration in PD: dopamine receptor agonists
may have a neuroprotective effect. This protection has been postulated to
result through a variety of mechanisms, including autoreceptor
stimulation, direct antioxidant effects, and decrease of subthalamic
nucleus excitotoxicity. Dr. Gimenez-Roldan cautioned that starting
treatment with agonists is not a blanket recommendation applicable to all
patients with PD, since several factors (such as age and cognitive
status) may steer the choice to levodopa instead for certain patients.
Dr. Andrew J. Lees of the National Hospital for Neurology and
Neurosurgery in Queen Square, London countered that treatment of PD
should start with levodopa in all but those patients with young-onset
PD.[18] He focused on the objective of maximizing quality of life
throughout this illness. He reminded the audience that levodopa maintains
its effectiveness much longer than any agonists. His main reason to avoid
using agonists in the first few years was that agonists are associated
with a higher rate of adverse effects.

This point was questioned by Dr. Rascol, who pointed out that the rate of
adverse effects was not significantly different between a dopamine
agonist and levodopa in the PELMOPET, CALM-PD, or O56 studies. However,
it is a widely accepted teaching that, for a given frequency of adverse
effects, levodopa is more potent than any agonist in relieving PD
symptoms. This belief is not, in fact, contradicted by the agonist
studies: as described above, in the 2 studies that compared the motor
examination scores, levodopa was more effective than the respective
agonist.
Dr. Lees' argument included consideration of an issue sometimes
overlooked in this debate: the first few years of the disease, though
marked by relatively mild symptoms, are also years during which many
patients continue working or have a chance to enjoy activities, such as
traveling, which they may need to give up later. Thus, treatment with a
more potent drug, as levodopa appears to be, may offer a more appreciable
improvement in quality of life than an agonist might. In part because of
this consideration, the question of whether levodopa is indeed more
"potent"- meaning providing greater relief for a given risk of adverse
effects and for a given ease of use-was discussed with some interest. No
one at the session offered a convincing explanation of why, in 2 of the
agonist studies, the motor examination scores improved more for patients
taking levodopa than for patients taking an agonist plus levodopa.

After the debates, the audience was asked to express their opinion via a
show of hands. Most audience members agreed that the new agonists are not
clearly better than the old ones. More surprisingly, most also supported
starting treatment of PD with levodopa rather than an agonist. This was
remarkable because the 3 studies showed a clear delay in the onset of
motor complications in patients treated with an agonist as initial
therapy. A possible explanation is that ease of use (some agonists
require a much slower titration of dose than levodopa before reaching the
same effectiveness) and rate of adverse effects, at least as experienced
by clinicians in their practice, may play a bigger role in a practicing
clinicians' choices than in the conclusions of a drug study.

Perhaps the most relevant comment, sobering as it was, was made by Dr.
Lees at the end of the discussion. He pointed out that when considering
the entire course of PD, which can span several decades, the first 5
years are usually marked by relatively minor symptoms that can be
controlled adequately with either levodopa or an agonist. As he put it,
"the first 5 years are easy" in terms of treatment choices. The much more
difficult period is the following years, during which motor fluctuations,
variation in response to levodopa, and the progression of symptoms
refractory to levodopa take a more serious toll on the quality of life of
patients with PD than in the first 5 years. Thus, without denying the
importance of making the best use of the treatment options that we have
for the initial period, he expressed hope that the search will continue
for better treatments for the more advanced stages of PD.