Source:            Askthedoctor-mailinglist
Date:                13 january 2002
Orig. source:    Neurology 2002;58:11-17
Orig. date:        9 january 2002

The following article appeared in Neurology, the official journal of the
American Academy of Neurology.
The article was modified by Dr. Lieberman so as to make it more readable by
lay people with PD.

Initiation of treatment for Parkinson’s disease.

Report of the Quality Standards Subcommittee of the American Academy of
Neurology.

J.M. Miyasaki, MD (lead author)

Abstract
In 1993, the last AAN Practice Parameter on medical treatment of Parkinson’s
disease (PD) concluded that levodopa was the most effective drug for
management of this disorder. Since then, a number of new compounds including
non-ergot dopamine agonists (DA) and sustained-release levodopa have been
released and studied. Thus, the issue of treatment in de nova PD patients
warrants reexamination.

Specific questions include:
1) does selegiline offer neuroprotection
2) what is the best agent with which to initiate symptomatic treatment in de
novo PD
3) is there a benefit of sustained release levodopa over immediate-release
levodopa?

Using evidence-based principles, a literature review was performed to
identify all human trials in de novo PD between 1966 and 1999. Based on this
review, the authors conclude:
1) Selegiline has very mild symptomatic benefit with no evidence for
neuroprotective benefit.
2) For PD patients requiring initiation of symptomatic therapy, either
levodopa or a DA can be used. Levodopa provides superior motor benefit but
is associated with a higher risk of dyskinesia.
3) No evidence was found that initiating treatment with sustained-release
levodopa provides an advantage over immediate-release levodopa.

NEUROLOGY 2002;58:11-17

Recent publications have compared levodopa directly to dopamine agonists
(pramipexole, ropinirole and cabergoline) in treatment of de novo
(previously untreated) patients with PD. These studies were a result of
concern that early use of levodopa might predispose patients to develop
long-term motor complications such as wearing off, dyskinesia, dystonia, and
on-off phenomenon.

Some studies have reported incidence of these complications as highs as 80%
in young patients and 44% in older patients after 5 years of levodopa
treatment. The frequency of dyskinesias alone is reported to range between
30-80% after 5 to 7 years of levodopa use. Dyskinesias may become severe
with pronounced interference in the performance of activities of daily
living.

Hence, quality of life can be negatively and significantly affected by
dyskinesias. Increasing problems with motor fluctuations also leads to use
of several different medications in combination, typically at higher doses.
Ideally, patients should not have to choose between accepting the
inevitability of dyskinesias or unacceptable levels of disability. The goal
of treatment should be to obtain an optimal reduction of parkinsonism with a
minimal risk of long-term side effects.

In an effort to decrease the risk of motor complications, attention has
turned to initial use of dopamine agonists as monotherapy. Historically,
dopamine agonists monotherapy has been thought to be poorly tolerated with
decreased efficacy and a delay in onset of symptomatic benefit in comparison
with levodopa. This may not be the case with newer agonists.

In addition, one of the theoretical benefits of dopamine agonists over
levodopa is a longer half-life resulting in less pulsatile stimulation of
dopamine receptors. This may reduce the risk of the development of
dyskinesias and motor fluctuations. The common occurrence of the wearing-off
phenomenon (end of dose bradykinesia) with immediate-release levodopa led to
the development of sustained-release levodopa. Whether motor complications
are influenced by initial symptomatic treatment of PD with sustained-release
levodopa versus immediate-release levodopa was investigated. Evidence
comparing these two levodopa preparations is evaluated.

Selegiline.

What is the role of selegiline in the treatment of early PD? A
neuroprotective benefit of selegiline through decreased free radical
production was proposed and resulted in the DATATOP clinical trial. An
interim analysis of the DATATOP trial demonstrated that selegiline reduced
the risk of developing disability requiring levodopa therapy by 50%.

The authors concluded, initially, that this was possibly consistent with a
neuroprotective effect. Further follow-up of the patients revealed a
symptomatic benefit of selegiline with a 17.2% absolute reduction in the
risk of requiring levodopa by selegiline compared with placebo (indicating
that selegiline did not slow the progression of PD rather that it had a mild
effect on masking the symptoms of  PD).

In a second study examining this issue, Palhagen and associates found a
4-month delay to requiring levodopa in those randomized to selegiline. The
rate of decline of the motor scores was significantly slower at 6 months.
Additionally, the rate of decline of motor scores from baseline to the end
of the washout was significantly slower for the selegiline-treated patients.
Since both groups found an initial decline in  disability during the 2-month
washout period, it must be concluded that symptomatic benefit at least
partially explained the reduced risk of requiring levodopa.

In addition, if selegiline had neuroprotective effects, those taking
selegiline for a longer period of time would be expected to show less
evidence of disease progression compared with those starting it later in the
course of the disease. Once levodopa was initiated, motor complications
would be expected to be less frequent in those who had received selegiline
than in those who had not. Neither of these expectations was realized,
further supporting the idea that the symptomatic effects of selegiline
accounted for the delay in the need for levodopa therapy.

One study raised the issue of the safety of selegiline. Lees and associates
in the United Kingdom reported a significant excess mortality in patients
receiving selegiline with levodopa alone (76 deaths from among 271 patients
treated with selegiline for several years) compared with those receiving
levodopa alone (44 deaths from among 249 treated with levodopa over a
comparable number of years). Concerns about the conduct and the conclusions
from this study were many.

An analysis of subsequent prospective trials in the United Kingdom with
long-term follow-up including patients with similar exposure to selegiline
as in the Lees study was performed. There was no difference in mortality
between selegiline and nonselegiline treatment groups (selegiline does not
increase the risk of death in PD).

The Parkinson Study Group (PSG) in the United States reported that there was
no difference in mortality in the 800 original DATATOP subjects who had been
assigned to selegiline after an average follow-up of 8.2 years. The
mortality rate observed in these patients was very similar to that expected
in the age- and sex-matched US population.

Conclusions.

Selegiline has mild symptomatic benefit. There is no convincing clinical
evidence for neuroprotective benefit with selegiline. There is no convincing
evidence for increased mortality with selegiline whether it is given in
combination with levodopa or as monotherapy.

Starting Treatment

When symptomatic therapy is required does levodopa or dopamine agonist offer
best control of motor symptoms? Once disability in PD requires treatment
with a dopaminergic agent, the choice of levodopa versus a dopamine agonist
has been arbitrary.  Decades of debate concerning this issue did not clarify
the choice because the  trials conducted in those years were inadequate to
answer the question.

In this evidenced based-review, three studies compared the effect of a
single agonist versus levodopa in the treatment of PD patients who were not
receiving dopamine agonist or levodopa therapy. Each-study was designed to
allow the addition of open-label levodopa to “rescue” patients who were not
doing well motorically.

The study of cabergoline (not available in the United States) versus
levodopa found that the motor portion of the UPDRS decreased by 40-50% with
both drugs during the first year of therapy. Overall, however, levodopa
appeared to be better than cabergoline for improvement. After 4 years in the
trial, levodopa subjects still showed an average of 30% improvement in motor
disability while patients treated with cabergoline showed a 22 %
improvement.

The study of ropinirole (Requip) versus levodopa found that for patients who
completed the study (5 years), levodopa treatment resulted in a greater
increase in motor improvement than did ropinirole treatment. They also
reported that, overall, there was no difference between the treatment groups
at 5 years with regard to score on the activities of daily living portion of
the UPDRS (this may be a better over-all measure of how people with PD are
doing).

The study of pramipexole (Mirapex) versus levodopa by the Parkinson Study
Group was assessed as being the best of the three studies. This study found
that after 23.5 months of treatment, levodopa resulted in a greater
improvement that pramipexole in both the motor and activities of daily
living portions of the UPDRS.

Conclusions.

Levodopa, cabergoline, ropinirole, and pramipexole are effective in reducing
motor and ADL disability in patients with PD who require dopaminergic
therapy. Levodopa is more effective than cabergoline, ropinirole, and
pramipexole in treating the motor and activities of daily living features of
PD.

When symptomatic therapy is required, does levodopa or a dopamine agonist
offer the most favorable long-term complication profile? All three studies
demonstrated that levodopa, cabergoline, ropinirole, or pramipexole have
efficacy in alleviating motor symptoms of PD. All three studies defined
motor complications differently.

The cabergoline study used a checklist of symptoms suggesting motor
fluctuations to determine the endpoint. The motor fluctuation abnormalities
had to be present on two subsequent study visit to be considered present.
Motor fluctuations in this study included wearing off, dyskinesias, and
random freezing (which were also evaluated in the ropinirole and pramipexole
studies). The motor complications checklist in the cabergoline study also
included nocturnal akinesia, early morning akinesia, “off” period freezing,
early morning dystonia, dose-related “off” period dystonia, and dose-related
“on” period dystonia. These latter items were not evaluated in the
ropinirole or pramipexole studies.

The cabergoline study found an absolute risk reduction of 12% for the
development of “motor complications” during the study comparing this agonist
(with or without levodopa rescue) to levodopa. The motor complication
endpoint was reached in 22% of patients treated with cabergoline versus 34%
treated with levodopa. The median duration of treatment was 3.7 years. At
the time of reporting, 35% of patients could be satisfactorily managed on
cabergoline alone. Patients included in this analysis were treated for at
least 3 years and up to 5 years. Adverse events were higher in the
cabergoline group (75%) versus levodopa (65%), with nausea being the most
common in both.

In the study of ropinirole versus levodopa, the primary endpoint was
dyskinesias rather than other types of motor complications. The absolute
risk reduction for dyskinesias after 5 years of treatment was 26% for the
ropinirole group (monotherapy or with the later addition of levodopa
adjunctive therapy). Adverse events were similar in the levodopa and
ropinirole monotherapy groups, with the two most common reasons for dropping
out of the study being nausea and hallucinations. The incidence of
hallucinations was higher in the ropinirole group ( 17%) than in the
levodopa group ( 6%), as was the incidence of edema of the legs (14%; versus
levodopa 6%) and drowsiness (27%; versus levodopa 19%).

However, dropout rates due to adverse events were no different in the two
treatment groups. Retention of patients in the 5-year study was 47% for the
ropinirole group and 50% for the levodopa group. Among patients who
completed the study and were originally randomized to ropinirole
monotherapy, 16% were maintained on ropinirole monotherapy for 5 years. A
lower percentage of the levodopa group required the addition of more
levodopa. The results demonstrate that initiation of treatment with
ropinirole and the later addition of levodopa as necessary resulted in a
significantly lower incidence of dyskinesia compared with levodopa alone.

The Parkinson Study Group study of pramipexole (Mirapex) versus levodopa
monotherapy in PD demonstrated similar findings. Motor complications,
defined as dyskinesias, wearing off, and on-off motor fluctuations, were
significantly less common in the pramipexole group (28%) versus
levodopa-treated patients (51%) at the end of 23.5 months. Motor
complications also occurred less frequently in the pramipexole-treatment
group in each of the four 6-month study periods. 32% of the originally
randomized group of pramipexole monotherapy patients were maintained on
monotherapy until the end of the study.

This study also examined the impact of treatment on the quality of life of
patients using the PD Quality of Life Scale and the European quality of
life. During the first 78 weeks of the trial, there was no difference in
quality of life measures for either treatment group. At 102 weeks, a
significant group difference in the PD Quality of Life in favor of the
levodopa group was detected.

More patients in the pramipexole group experienced drowsiness,
hallucinations, and edema compared with those in the levodopa group. As
noted in the 1993 practice parameter on this subject, treatment with
dopamine agonists is more costly than the use of levodopa. This remains
true.

Conclusions.

Cabergoline, ropinirole, pramipexole treatment of PD patients requiring
dopaminergic therapy results in fewer motor complications wearing off,
dyskinesias, on-off motor fluctuations) than levodopa treatment after 2.5
years of follow-up. Cabergoline, ropinirole, and pramipexole treatment of PD
patients requiring dopaminergic therapy is associated with more frequent
hallucinations, drowsiness,  and edema than levodopa therapy.

Recommendations.

In patients with PD who require the initiation of dopaminergic treatment,
either levodopa or a dopamine agonist may be used. The choice depends on the
relative impact of improving motor disability (better with levodopa)
compared with the lessening of motor complications (better with dopamine
agonists) for each individual patient with PD.

Sustained-release versus immediate release levodopa:

When initiating levodopa therapy, which formulation should be
used-immediate-release or sustained-release levodopa? Only one study
compared sustained-release and immediate-release formulations of levodopa in
a prospective, randomized, double-blind manner. The 5-year study (“CR
 First”) had an overall low rate of dyskinesias (20% immediate-release
Sinemet versus 21% in the Sinemet CR group.

The only difference detected between the treatment groups was a greater
improvement in activities of daily living scores in the Sinemet CR group.
The results of this study do not demonstrate sufficient differences to
recommend controlled-release levodopa over immediate-release levodopa when
initiating levodopa treatment.

Conclusions.

When initiating therapy with levodopa, there is no difference in the rate of
motor complications between immediate-release levodopa and sustained-
release levodopa.

Recommendations.

For patients with PD in whom levodopa treatment is being instituted, either
an immediate-release or sustained-release preparations may be considered.

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