High doses of pergolide improve clinical global impression in advanced Parkinson's disease—A...

High doses of pergolide improve clinical global

impression in advanced Parkinson’s

disease—A preliminary open label study

Guy Arnold a,*, Thomas Gasser b,2, Alexander Storch c,3,Axel Lipp a, Andreas Kupsch a, Hans-Peter Hundemer d,

Johannes Schwarz c,1

a Department of Neurology, Charite, University Hospital Berlin, Schumannstraße 20/21,

D-10117 Berlin, Germanyb Department of Neurology, Ludwig-Maximilians-University, D-81377 Munich, Germany

c Department of Neurology, University of Ulm, D-89081 Ulm, Germanyd Lilly Deutschland GmbH, D-61350 Bad Homburg, Germany

Received 18 August 2004; received in revised form 11 April 2005; accepted 14 April 2005

Available online 18 July 2005

Abstract

We evaluated the efficacy and safety of high-dose pergolide treatment in patients with moderate

to severe Parkinson’s disease (PD) in an open-label multicenter clinical trial. The primary

objective was to assess the amount of reduction in levodopa, the improvement in Unified

Parkinson’s Disease Rating Scale (UPDRS) and adverse reactions. We treated 32 patients with

PD presenting with motor fluctuations. Pergolide treatment started with a dose escalation period of

12 weeks followed by a 12-week continuation period. Pergolide doses were increased up to a

maximum of 12 mg/day in combination with a simultaneous decrease of levodopa doses in 100 mg

steps. Levodopa was reduced from 500 mg/day (median) to 250 mg/day. Mean UPDRS part III

improved significantly ( p = 0.01). Clinical global impression improved significantly after 24

weeks ( p < 0.01). Most frequent adverse events were hallucinations, asthenia, anxiety, abdominal

pain, and peripheral edema. Twenty-two patients finished the complete study according to

protocol. A possible relationship to the study medication was assumed for two serious adverse

www.elsevier.com/locate/archger

Archives of Gerontology and Geriatrics 41 (2005) 239–253

* Corresponding author. Tel.: +49 30 450 560 102; fax: +49 30 450 560 932.

E-mail address: [email protected] (G. Arnold).1 Present address: Department of Neurology, University Hospital, D-04103 Leipzig, Germany.2 Present address: Hertie-Institute for Clinical Brain Research, Neurodegeneration, University of Tuebingen,

D-72076 Tuebingen, Germany.3 Present address: Department of Neurology, University Hospital, D-01307 Dresden, Germany.

0167-4943/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights reserved.

doi:10.1016/j.archger.2005.04.002

events reporting psychosis. We conclude that high doses of pergolide are efficacious in advanced

stages of PD if given in appropriate regimens.

# 2005 Elsevier Ireland Ltd. All rights reserved.

Keywords: Parkinson’s disease; Dyskinesias; Levodopa-related motor fluctuations; Dopamine agonist; Adverse

events

1. Introduction

Levodopa is still considered to be the therapy of choice in patients with advanced

idiopathic PD. Levodopa is effective in the vast majority of patients, but a high incidence of

adverse effects in long-term use (usually after 3–5 years of continuous use) is observed

(Fahn, 1992). As the duration of levodopa therapy progresses, increasing numbers of

patients experience response fluctuations (on/off phenomena) and other motor

complications, such as dyskinesias.

The major risk factor for these adverse effects appears to be duration and dosage of

levodopa therapy (Reardon et al., 1999).

Pergolide mesylate is a synthetic ergot derivative dopamine agonist with affinity at both

D1 and D2 dopamine receptors (Fuller and Clemens, 1991). Pergolide has a long half-life of

about 21 h in Parkinsonian patients (Thalamas et al., 2001), thus providing persistent

stimulation of dopamine receptors more akin to the normal physiological condition than the

intermittent stimulation of D1 and D2 receptors provided by standard preparations of

levodopa. A large number of open and placebo-controlled studies with pergolide have been

conducted in patients suffering from PD since 1980 (for review, see Langtry and Clissold,

1990; Clarke and Speller, 2000a,b). In many of these studies, pergolide, when used as adjunct

therapy to levodopa, allowed a significant reduction in the dosage of levodopa (Tanner et al.,

1982; Ilson et al., 1983; Klawans et al., 1983; Gonce and Delwaide, 1985) and decreased

patients’ off’ time (Lang et al., 1982; Tanner et al., 1982). Based on two studies with patients

in early stages of the disease (Barone et al., 1999; Oertel et al., 2001), pergolide was later

registered for mono-therapy in PD in several countries. The favorable effects of the treatment

seemed to increase with the dosage of pergolide and the dose reduction of levodopa.

At present, levodopa seems to be the most effective substance to treat the symptoms of

Parkinson’s disease, but in this drug leads to motor fluctuations and involuntary dyskinesias

in almost all patients during the course of the disease. In contrast, physicians estimated

pergolide to be less effective with respect to efficacy, but scientific data showed a

significantly decreased incidence of dyskinesias and motor fluctuations. The risk of

psychiatric adverse events, however, seemed to be higher.

The aim of the present open label study was to evaluate

(1) the extent of levodopa reduction allowed by the increase of pergolide doses (up to

pergolide mono-therapy);

(2) the improvement in motor fluctuation and dyskinesia scores of the Unified Parkinson’s

Disease Rating Scale (UPDRS) part IV associated to the levodopa dose decrease and

pergolide dose increase; and

G. Arnold et al. / Archives of Gerontology and Geriatrics 41 (2005) 239–253240

(3) whether a levodopa reduction up to pergolide mono-therapy provided at minimum the

same symptomatic relief as measured by UPDRS part III.

2. Methods

2.1. Study design

This trial was a 26-week, multi-center prospective open clinical trial in patients with

advanced PD in Hoehn and Yahr stages 2–4 (Hoehn and Yahr, 1967). The study consisted

of three periods: a 2-week observation period to assess patients’ suitability for the trial, a

12-week period with a fixed titration scheme and a 12-week continuation period. At the

start of the titration period, all patients pre-treated with bromocriptine, lisuride, a-

dihydroergocryptine or ropinirole as dopamine agonists were switched to pergolide using

an equivalent starting dose of pergolide (bromocriptine, 1:10 or 1:15; lisuride, 1:1; a-

dihydroergocryptine, 1:60; ropinirole, 1:3). Since no comparative trials with pergolide are

published, the ratio had to be predefined on an experience basis. Telephone based visits

during this period were conducted every 14 days (�3 days). From visits 2 to 8, the dosages

of levodopa/pergolide medication were adjusted weekly or bi-weekly. In this period, the

dose of pergolide was increased in 0.5 mg steps before and 1 mg steps after reaching a daily

dose 3 mg pergolide and up to a maximum dose of 12 mg/day. The dose of levodopa was

decreased in steps of 100 mg. Adjustments of the titration scheme according to individual

clinical needs were allowed; for example, a weekly adjustment by 0.5 mg instead of 1 mg.

If the patient had shown no further clinical improvement, the lowest dose level associated

with the best clinical judgment was administered until the end of the titration period.

Patients who, in the opinion of the investigator, deteriorated clinically and whose

medication had been adjusted either up or down without success in order to ameliorate the

deterioration were discontinued. In the subsequent 12-week continuation period, the dose

of the last 2 weeks in the titration period was to be maintained without further changes if

clinically possible. Additional dose adjustments necessary to keep the best UPDRS part III

and/or IV score had to be reported. The patients were assessed twice in the continuation

period: after 6 weeks by a telephone contact and at the end of the treatment (week 24) by a

visit in the study center.

Prior to screening, written informed consent was obtained from all patients. The

protocol and its amendments were submitted to and approved by the respective

independent ethics committee of the universities involved. The study was conducted

according to the declaration of Helsinki.

2.2. Patients

We included 32 patients with advanced PD with motor fluctuations and a disease stage

of 2.5–4 on the Modified Hoehn and Yahr Staging Scale (Hoehn and Yahr, 1967). All

patients had received previous treatment with levodopa/benserazide or levodopa/

carbidopa with a dose of levodopa of at least 200 mg/day and up to 1 g/day that had been

stable for a minimum of 3 months prior to the study. Previous treatment also included

G. Arnold et al. / Archives of Gerontology and Geriatrics 41 (2005) 239–253 241

either pergolide, bromocriptine, lisuride, dihydroergocryptine or ropinirole, and might

have included selegiline, which had to be stable for a minimum of 1 month before

entering the study. Patients with a concurrent or past diagnosis of malignant melanoma, a

history of severe psychosis including schizophrenia, a history of severe depression, a

past or current history of nonfebrile seizure, an active gastric or duodenal ulcer or a

history of ulcer within the previous 12 months, presenting with clinically significant or

unstable medical conditions (including serious hepatic, cardiovascular, pulmonary, or

renal disease), or with a serum concentration of any enzyme greater than twice the upper

limit of the reference range of the study laboratory, or a serum creatinine concentration

greater than 1.5 times the upper limit of the reference range (age and sex corrected) of

the study laboratory at admission were excluded. Finally, pregnant women, lactating

women, or women of childbearing potential who were not using medically accepted

means of contraception were excluded.

Concomitant medications not allowed during the study were anticholinergics,

amantadine, MAO-A inhibitors, tricyclic antidepressants, meperidine, neuroleptics,

anticonvulsants and a-methyl dopa. Treatment with antihistamines was prohibited during

the observation period and was restricted to 10 days of cumulative use during the titration

period. Domperidone was allowed as needed.

2.3. Outcome measures

The primary efficacy measure of the study was the extent of levodopa dose reduction

allowed by the increase of pergolide doses (up to pergolide mono-therapy). Secondary

objectives of the study were to determine whether a levodopa reduction up to pergolide

mono-therapy provided at minimum the same symptomatic relief as previous therapy

measured by UPDRS part III, to evaluate the improvement in motor fluctuation and

dyskinesia scores of UPDRS part associated to the levodopa dose decrease and pergolide

doses increase, and to assess safety through evaluation of adverse events, laboratory tests

and vital signs.

2.4. Statistical analysis

In a multicenter double blind placebo-controlled trial of Pergolide as an adjunct

to levodopa in PD, the drop-out rate was 15.9% for pergolide (Olanow et al.,

1994). Therefore, a relative drop-out rate of 20% was calculated. Due to clinical

experience we assumed a 25% reduction in L-dopa dose in more than 80% of pergolide

treated patients. Based on these data and using the method of confidence limits of

an observed frequency for a binomially distributed population, approximately 30

patients were required to detect a statistically significant effect at a one sided 5%

probability. For each patient, the achieved reduction of levodopa dosage was calculated

and presented as median values with 95% confidence intervals (CI). An analysis by

means of Wilcoxon matched pairs signed rank test was performed to evaluate the success

in levodopa dose reduction. The null hypothesis for was that pergolide is not effective

in levodopa dose reduction. The alternative hypothesis was that pergolide is effective in

levodopa dose reduction.


Intent-to-treat analyses (using a last observation carried forward [LOCF] method) were

performed on the data collected for the secondary efficacy variables. Changes from

baseline for all secondary efficacy variables were evaluated by Wilcoxon signed rank tests.

Data were expressed as mean plus/minus standard deviation.

3. Results

3.1. Demographics and baseline characteristics

We included 33 patients with moderate to severe PD. Of these, 32 received study

treatment for at least 4 weeks and were included in the intent-to-treat analysis of all efficacy

parameters. The demographic baseline characteristics and baseline Hoehn and Yahr

staging of these patients are presented in Table 1. Anti-Parkinson medication given in

addition to pergolide is summarized in Table 2.

During study treatment, 10 patients (10/32, 31%) discontinued the study: five patients

during the titration phase and five patients during the continuation phase. Table 3 presents

time and reason for drop-outs.

3.2. Primary objective—levodopa dose reduction

Prior to study start, levodopa was administered to the patients at a median dose of

500 mg/day (95% CI: 300–600 mg). At the end of the titration phase (week 12), a median

dose of 250 mg (95% CI: 200–400 mg) was reached, indicating a decrease of 44% from

baseline (95% CI: �14% to �63%; Wilcoxon signed rank test: p < 0.01). The median


Table 1

Demographic variables

Intent-to-treat group

Race

Caucasian 32 (100%)

Sex

Male 21 (66%)

Female 11 (34%)

Age (years)

Mean � S.D. [minimum, maximum] 60.1 � 10.1 [34, 76]

Hoehn and Yahr stage

0 (no signs)

1 (unilateral disease)

1.5 (unilateral disease + axial involvement)

2 (bilateral disease without impairment of balance)

2.5 (mild bilateral disease with recovery on pull test) 16 (50%)

3 (mild to moderate bilateral disease) 11 (34%)

4 (severe disability) 5 (16%)

5 (wheelchair-bound or bedridden)

value of levodopa dosage remained unchanged during the continuation period until end

of study (week 24: median, 250 mg; change, �49%; 95% CI: �14% to �58%;

Wilcoxon signed rank test: p < 0.01). The median levodopa dose over time is displayed

in Fig. 1.

3.3. Pergolide dose

The patients started study treatment with a median dose of 2.5 mg pergolide (95% CI:

1.8–3.0 mg). Until the end of the titration phase this dose was increased up to a final

median dose of 6.5 mg/day at week 12 (95% CI: 5.0–8.5 mg) resulting in a 140% median

increase of the pergolide dose compared to baseline (95% CI: 67–300%; Wilcoxon signed


Table 2

Concomitant anti-Parkinson drugs

Drug No. of patients (N = 32)

Levodopa + benserazide 21 (66%)

Levodopa + carbidopa 18 (56%)

Selegiline 9 (28%)

Amantadine 2 (6%)

Budipine 1 (3%)

Ropinirole 1 (3%)

Metixene 1 (3%)

Tolcapone 1 (3%)

Dihydroergocryptine 1 (3%)

Bromocriptine 1 (3%)

Number of patients with anti-Parkinson drugs 32 (100%)

Number of entries 56

Mean number of entries per patient 1.8

Table 3

Dropouts (N = 10 patients)

Last visit Days of study treatment Reason

3 16 Lack of compliance

5 42 Protocol criteria not met: unallowed medication

(amantadine, metixene) in the last 4 weeks before start of study

(medication was not discontinued)

8 77 Patient decision

8 89 Lack of efficacy, patient and physician perception

8 91 Lack of efficacy, physician perception

9 105 SAEa: hospitalization for psychosis

10b 154 SAEa: hospitalization for anxiety

10b 147 Lack of efficacy, patient perception

10b 130 SAEa: hospitalization for hallucinations and psychosis

10b 168 AEa: syncopea SAE: serious adverse event, AE: adverse event.b Study discontinuation after visit 9.

rank test: p < 0.01). The median value of pergolide doses increased further during the

continuation period (week 24: median, 7.25 mg/day; change, 167%; 95% CI: 100–350%;

Wilcoxon signed rank test: p < 0.01; see Fig. 2 for a display of the median pergolide dose

over time).

3.4. Secondary objectives—UPDRS scores

PD symptomatology was assessed by UPDRS scores. An overview of UPDRS total

score and subscore results can be found in Table 4.

UPDRS part III (motor examination, items 18–31) results as measured in the ON phase

improved significantly throughout the study until the end of the 24-week treatment period

(baseline: 25.8 � 13.2, end of study: 21.0 � 14.9, change: �4.8 � 14.7; Wilcoxon signed


Fig. 2. Median pergolide dose during study treatment in milligrams. (*) Significant difference compared to

baseline ( p � 0.05, Wilcoxon signed rank test, test was only calculated for weeks 12 and 24).

Fig. 1. Median levodopa dose during study treatment in milligrams. (*) Statistically significant difference

compared to baseline ( p � 0.05, Wilcoxon signed rank test, test was only calculated for weeks 12

and 24).

rank test: p = 0.01; see Fig. 3). Significant reductions in the UPDRS part III were already

present after 6 and 12 weeks of treatment (week 6: p = 0.03, week 12: p < 0.01, Wilcoxon

signed rank test). Additionally, a tremor analysis of UPDRS part III was performed (items

20 + 21 in patients with positive tremor scores at baseline, N = 22). A significant reduction

of tremor related scores was observed at the final visit compared to baseline (baseline:

4.0 � 3.8, final visit: 1.9 � 2.1, change: 2.2 � 3.0).

UPDRS part I (mentation, behavior and mood, items 1–4) slightly increased during

study treatment until the end of the 24-week treatment period (Wilcoxon signed rank

test: p = 0.20 compared to baseline). In contrast, UPDRS part II (activities of daily

living, items 5–17) tended to decrease during the 24-week treatment period (Wilcoxon

signed rank test: p = 0.19 compared to baseline). This decrease compared to baseline was

most pronounced at week 12 ( p < 0.01, Wilcoxon signed rank test). UPDRS part IV

(complications of therapy, items 32–42) decreased slightly during study treatment until

the end of the treatment period (week 24: Wilcoxon signed rank test: p = 0.51 compared

to baseline).


Table 4

Mean UPDRS, clinical global impression (CGI) and patients global impression (PGI) scores

Score Baseline Week 6 Week 12 Week 24

UPDRS total score 46.1 � 20.6 39.8 � 17.1* 39.1 � 16.7* 40.9 � 22.4

UPDRS I (mentation, behavior and mood) 1.4 � 1.4 1.2 � 1.6 1.8 � 1.9 1.8 � 1.9

UPDRS II (activities of daily living) 13.3 � 5.9 11.4 � 6.2 12.5 � 6.6 12.8 � 7.4

UPDRS III (motor examination) 25.8 � 13.2 21.7 � 11.6* 19.9 � 10.6* 21.0 � 14.9*

UPDRS IV (complications of therapy) 5.7 � 3.8 5.5 � 3.5 4.8 � 3.3 5.3 � 3.3

CGI-improvement 0.13 � 0.42 0.52 � 0.72* 0.38 � 0.94* 0.59 � 1.10*

PGI-improvement – 0.41 � 0.80* 0.16 � 1.05 0.4 � 1.19*

* Statistically significant difference (Wilcoxon signed rank test, p � 0.05) compared to Baseline (except for

CGI improvement: compared to admission).

Fig. 3. UPDRS III score (motor examination) during study treatment. (a) UPDRS III score decrease signifies

improvement of motor function. (*) Statistically significant difference compared to baseline ( p � 0.05, Wilcoxon

signed rank test).

For the UPDRS total score, the results at the final study visit (week 24) indicated a trend

to lower values compared to baseline (baseline: 46.1 � 19.0, end of study: 40.9 � 22.4,

change: �5.3 � 21.1; Wilcoxon signed rank test: p = 0.09). However, a significant

reduction from baseline was present after 6 and 12 weeks of study treatment ( p < 0.01,

Wilcoxon signed rank test).

3.5. Mono-therapy

Four patients could be down-titrated to mono-therapy with pergolide. The mean initial

levodopa dose was 720 mg/day. The mean pergolide dose could be increased from 2.3 to

9 mg. In two patients, however, the increase of pergolide and the cessation of levodopa

were not tolerated for longer than 1 week. Small doses of levodopa had to be introduced

with much higher pergolide doses; in these patients, UPDRS (part IV) decreased form an

initial mean of 4.66 to 2 at the last observation.

3.6. CGI-improvement

Clinical global impression (CGI)-improvement ratings obtained after observation

period (baseline versus admission) demonstrated unchanged findings for the majority of

patients (26/32 patients, 81%) and a minimal improvement in five patients (16%)

(Wilcoxon signed rank test: p = 0.22). Compared to admission a significant, positive

change in CGI-improvement was documented after 6, 12, and 24 weeks of study treatment

(Wilcoxon signed rank test: week 6: p < 0.01, week 12: p = 0.03, week 24: p < 0.01)

(Figs. 4 and 5).

3.7. PGI-improvement

Compared to baseline, a significant improvement in the patients global impression

(PGI)-improvement scale was documented after 6 and 24 weeks of study treatment

(Wilcoxon signed rank test: week 6: p < 0.01, week 12: p = 0.43, week 24: p = 0.05).


Fig. 4. Mean change (with S.D.) of the clinical global impression (CGI)-improvement score compared to

admission. (a) Modified CGI-improvement scale: +3, very much improved; �3, very much worse.

3.8. Secondary objectives—safety and tolerability

In total, 60 treatment-emergent adverse events were reported in 21 (64%) of all (N = 32)

patients receiving study treatment. Treatment-related adverse events occurred in 19/32

(59%) of the patients (Table 5). The following events were documented most frequently:

hallucinations (six events in six patients, 18%), asthenia (five events in four patients, 12%),

anxiety (four events in three patients, 9%), peripheral edema (three events in three patients,

9%) and abdominal pain (three events in two patients, 6%). Sixteen adverse events (16/60,

27%) were psychiatric disorders reported by 11 patients (11/32, 34%). Single findings were

documented in four other body systems (7% of the events in 12% of the patients).

Nine treatment-emergent serious adverse events in five patients (16%) occurred during

the study. Three patients suffered from psychiatric disorders, one patient from


Fig. 5. Mean change (with S.D.) of the patients’ global impression (PGI)-improvement score compared to

baseline. (a) Modified PGI-improvement scale: +3, very much improved; �3, very much worse.

Table 5

Adverse eventsa by body system (number of events occurring)

Events (body system) No. of events %

Psychiatric disorders 16 27

Body as a whole—general disorders 12 20

Gastro-intestinal 11 18

Metabolic and nutritional disorders 4 7

Central and peripheral nervous system disorders 3 5

Respiratory system disorders 3 5

Urinary system disorders 3 5

Cardiovascular disorders, general 2 3

Skin and appendages disorders 2 3

Neoplasms 1 2

Endocrine disorders 1 2

Resistance mechanism disorders 1 2

Vascular (extracardiac) disorders 1 2

Total 60 100a Treatment-emergent adverse events.

gastrointestinal disorders, and in one patient a bronchial carcinoma was diagnosed. Three

patients discontinued study treatment because of serious adverse events: two cases of

psychosis considered as probably related to study medication, one case of anxiety

considered as not related to study medication. Additionally, one patient discontinued

because of a non-serious adverse event (syncope with moderate intensity).

4. Discussion

We investigated the effect of high doses of pergolide on levodopa reduction in 32

Parkinsonian patients with motor fluctuations. This is, to our knowledge, the first report to

show in a prospective manner the amount of levodopa reduction achieved by high doses of

pergolide. Simultaneously, clinical improvement was measured by UPDRS part III and

CGI/PGI global impression scales.

The rationale to aim for a pronounced levodopa reduction was the observation that

increasing numbers of patients experience response fluctuations (on/off phenomena) and

other motor complications, such as dyskinesias, as the duration of and cumulative dosage

of levodopa therapy progress. Dopamine agonists like pergolide bear little or no risk of

motor fluctuations and dyskinesias, at least during the first years of treatment.

Facca and Sanchez-Ramos (1996) were the first to report marked clinical improvement

following high doses of pergolide and cessation of levodopa in single patients, whereas

Mizuno’s study (Mizuno et al., 1995) mixed mono-therapy with pergolide and combination

therapy with pergolide and levodopa. In an open mono-therapy trial, the authors could

maintain mid stage Parkinsonian patients for 2 years (38 of 62) and 4 years (20 of 62),

respectively. Schwarz et al. (1997) presented a retrospective analysis of three patients.

These observations were confirmed in a larger group of patients (Trenkwalder et al., 2000).

Based on these data, we planned a prospective clinical trial to evaluate the effect of high-

dose pergolide on levodopa dosage and clinical presentation. This trial was performed

without a control group based on the results of several placebo-controlled trials (Ahlskog

and Muenter, 1988; Olanow et al., 1994; Hely et al., 1996), which demonstrated that a

decrease in daily levodopa intake and a simultaneous escalation of dopamine receptor

agonists leads to an improvement of motor fluctuations.

4.1. Primary endpoint

The primary endpoint—a significant decrease in daily levodopa intake—was reached

by increasing the daily pergolide dose to a median dose of 7.25 mg. Pergolide mono-

therapy, however, was achieved in only four patients, representing 12.5% of all patients in

the intent-to-treat analysis. Based on early studies with pergolide (Lang et al., 1982;

Lieberman et al., 1983), the predefined maximal daily dose used in the present study was

12 mg, which might have been too low, as beneficial effects of pergolide continue using

doses up to 24 mg daily (data not published). Nevertheless, a series of secondary endpoints

has been met in this study, indicating not only the possibility of a levodopa dose reduction,

but also the achievement of a clinical improvement of PD with high-dose pergolide

treatment.


4.2. Secondary efficacy endpoints

Most early studies with pergolide as adjunct therapy to levodopa included patients

without previous dopamine receptor agonist therapy (Ahlskog and Muenter, 1988; Olanow

et al., 1994) and reported a dose reduction of levodopa of about 30%, a significant

improvement in motor scores, clinical fluctuations, and on-time. In contrast to these

studies, we aimed to statistically significantly improve the disability caused by PD in

patients, being already treated with dopamine receptor agonists. This more ambitious goal

was reached with respect to UPDRS part III motor symptoms for the whole continuation

period as well as for a tremor subanalysis, but not for clinical fluctuations as measured by

UPDRS part IV. This latter finding is in contrast to the retrospective study of Trenkwalder

et al. (2000). They were able to show a marked reduction in off time and dyskinesias as

documented in patient diaries. One explanation of this difference could be in the superior

sensitivity of diaries compared to UPDRS IV. Another explanation of the fact that we found

an improvement only with respect to UPDRS III, but not to UPDRS IV might be attributed

to increased overall dopaminergic stimulation. This argument, however, cannot neither be

proven nor ruled out. There are no systematic data on the equivalent doses of dopamine

receptor agonists and levodopa. Simultaneously, there exists a series of recommendations

on equal efficacy of levodopa and most dopamine agonists, which, however, are published

in non-scientific brochures and ‘‘guidelines’’ and lack scientific evidence. A prospective

study to investigate the effect of ropinirole and bromocriptine (Gimenez-Roldan et al.,

2001) found a comparable effect in only one of three presumed dosages, but even the best

fit failed in 21%. With respect to levodopa and dopamine receptor agonists, one could argue

that levodopa has a much more linear dose–effect relationship than agonists, i.e., in higher

doses, which are investigated in the present study. The effect of this class of drugs may be

less pronounced during up-titration. This problem occurred for instance during the study of

Rinne et al. (1998), who had to re-calculate the presumed equivalence of levodopa and low

to medium doses of cabergoline in favor of levodopa. In our calculation, we suggested an

equivalence of 2.5 mg pergolide to 250 mg levodopa. Our results point out an equivalence

of 5 to 250. This might be the reason, why mono-therapy was achieved only in four

patients, although with a dramatic reduction of motor fluctuations. Two patients stopped

mono-therapy later on with subjective impression of a insufficient efficacy, but continued

on high pergolide doses and reduced motor fluctuations.

4.3. Safety and tolerability

Within the time period of 24 weeks evaluated in the present study, we can consider high

doses of pergolide as safe. The side effects observed most frequently and clinically most

relevant were psychiatric complications such as psychosis, hallucinations and anxiety,

which were observed in 11 patients during the study. Psychiatric problems, however, are

one of the most frequent problems in patients with PD and are most difficult to treat. This is

reflected by the fact that 11 patients complained about psychiatric problems already at

inclusion. Therefore, we would like to point out that—reversible—psychiatric adverse

events are one hallmark during the treatment with high doses of pergolide, but are also a

common problem during advanced stages of PD in general.


Since the report of Frucht et al. (1999), physicians became aware of the problem of

excessive daytime sleepiness in Parkinsonian patients. During the last year the proposal of

‘‘sleep attacks’’ had been criticized, but vehicle accidents had been reported under

pergolide therapy as well (Arnold, 2000). The present study was conducted prior to the

publication of Frucht, but careful data analysis revealed no hints of ‘‘increased tiredness’’,

‘‘excessive daytime sleepiness’’, ‘‘sleep attacks’’, ‘‘sleeping at the wheel’’ or other possible

signs of sleep disturbances. We concede that our study had neither the intention nor the

power to show the effect of pergolide on daytime sleepiness, but we would like to stress the

point that even high doses of pergolide do not seem to induce tiredness. A dose dependent

effect on tiredness had been orally reported for other (non-ergoline) dopamine receptor

agonists (data not published).

We observed neither pleural nor peritoneal fibrosis in our study, a severe adverse event,

which occurs rarely under treatment with ergoline derivatives. These adverse events occur

with pergolide therapy (Shaunak et al., 1999) and might be more frequent with higher daily

doses. Therefore, we recommend monitoring ECG and sedimentation rates during long-

term high-dose pergolide therapy.

4.4. Conclusion

This first prospective study on high doses of pergolide in advanced stages of PD

provides evidence that this therapeutic strategy is efficacious and safe, if special attention is

paid for hallucinations and psychosis. The major clinical relevance was observed in motor

symptoms (UPDRS part III) and the clinical global improvement (CGI, PGI). Patients

treated with neuroleptics should be excluded from this strategy as they were during this

study. Therapeutic alternatives are sparse and include a regimen with increasing levodopa

doses leading to uncontrollable fluctuations and ‘‘yo-yoing’’. Continuous infusions of

apomorphine (Frankel et al., 1990) principally bear the same risks and limitations and are

restricted to specialized centers. Stimulation of deep brain structures as thalamus and sub-

thalamic nucleus, first described by Benabid et al. (1991), will be available only for a

minority of patients. Future research should address high-dose pergolide treatment of

patients in earlier stages of PD without fluctuations or should evaluate the safety and

efficacy of even higher pergolide doses.

Acknowledgements

The statistical support of T. Lorenz is gratefully acknowledged. This study was

supported by a research grant of Lilly Deutschland GmbH, Bad Homburg, Germany.

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