Dopamine agonists in the treatment of Parkinson's disease
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REVIEW
CME CREDIT
Uli
Dopamine agonists in the treatment
of Parkinson's disease
R A J E S H PAHWA, MD, A N D W I L L I A M C. KOLLER, MD, PHD
S PARKINSON'S DISEASE
The dopamine agonists bromocriptine and per- progresses, dopamine
golide are useful adjuvants to levodopa in treating Parkinson's replacement therapy
disease. Used this way, they can produce clinical improve- with levodopa becomes
ment and can often permit lowering of the levodopa dosage. less and less effective, owing to a
decreasing threshold for dose-lim-
Bromocriptine or pergolide can be used as initial iting side effects. Drugs with a dif-
monotherapy in Parkinson's disease. When used as an adju- ferent mechanism of action might
vant to levodopa therapy, these drugs can result in clinical im- offer a way to avoid this problem,
provement and a decreased levodopa requirement. To or might work synergistically with
levodopa and at least delay the lat-
avoid side effects, the starting dosage should be low (1.25 mg
ter's side effects. This paper re-
per day of bromocriptine or 0.05 mg of pergolide) and should
views recent work with the
be increased slowly. The standard daily dose of bromocriptine
dopamine agonists bromocriptine
ranges from 7.5 to 60 mg, and of pergolide, from 0.75 to 4 mg.
and pergolide.
Combination therapy with low dosages of levodopa and a
dopamine agonist may also decrease the incidence of side ef-
fects of both agents. WHY DOPAMINE AGONISTS
ARE NEEDED
INDEX TERMS: PARKINSON'S DISEASE; DOPAMINERGIC AGENTS
CLEVE CLIN J MED 1995; 62:212-217 Levodopa is the most effective
drug currently available for Park-
inson's disease,1 but it is not ideal:
dyskinesia, dystonia, "wearing-off'
From the Department of Neurology, the University of Kansas Medical
Center. phenomena, "end-of-dose deterio-
Address reprint requests to R.P., Department of Neurology, University of ration," and, occasionally, abrupt
Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160. ("random on-off') motor fluctua-
tions2 are complications of long-
term treatment. The exact mecha-
nism for the development of
motor fluctuations is unknown.
One possible explanation is that,
as Parkinson's disease progresses,
the number of dopaminergic cells
projecting to the striatum de-
212 CLEVELAND CLINIC IOURNAL OF MEDICINE VOLUME 62 • NUMBER 4
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creases, as does dopa-decar- TABLE 1
boxylase activity,3 resulting DOPAMINE AGONISTS CURRENTLY AVAILABLE IN THE UNITED STATES
in a reduced ability to syn-
Receptor Plasma half-life Dose
thesize dopamine from Agonist profile (hours) (mg/day) Preparations
levodopa, store it, and re-
Bromocriptine D1 antagonist 3-7 7.5-60 2.5-mg tablets
lease it. Hence, each dose D2 agonist 5.0-mg capsules
of levodopa has a shorter Pergolide* D1 agonist 12-24 0.75-4 0.05-mg tablets
clinical response, resulting D2 agonist 0.25-mg tablets
in motor fluctuations. An- 1.0-mg tablets
other reason may be a * Pergolide is approximately 10 times as potent as bromocriptine
change in the sensitivity or
number of postsynaptic
dopamine receptors.4 Similarly, dyskinesia and reaches the systemic circulation. Its major route of
dystonia may result from the actions of dopamine elimination is biliary, and 98% is excreted in the
on supersensitive postsynaptic striatal receptors.5 feces. Its plasma half-life is 6 hours.12,13
Alternative drugs that do not require intraneuro- In patients with mild to moderate Parkinson's
nal activation within the impaired nigrostriatal disease, bromocriptine in low dosages (less than 30
dopamine pathway might avoid these problems. mg per day) may be used as adjuvant to levodopa.
Dopamine agonists activate the dopamine receptors Bromocriptine should be introduced at 1.25 mg per
directly and have proven beneficial in Parkinson's day and the daily dose increased by 2.5 to 5.0 mg
disease. Multiple dopamine receptor subclasses have each week, as tolerated. A decrease in the dosage of
been identified; however, dopamine agonists mainly levodopa may be necessary. The daily dose of bro-
affect the D1 and D2 subtypes.6 Stimulation of D1 mocriptine is 7.5 to 60 mg per day.
receptors activates adenylate cyclase, leading to the
accumulation of cyclic adenosine monophosphate Bromocriptine as monotherapy
(cAMP). Stimulation of D2 receptors, on the other There are conflicting reports regarding bro-
hand, inhibits cAMP formation.7 Although D2 re- mocriptine monotherapy in Parkinson's disease.
ceptors appear to be more important than D1 recep- Teychenne et al14 found dosages of less than 10 mg
tors in mediating parkinsonian symptoms, com- per day effective in controlling parkinsonian symp-
bined D1 and D2 agonists have an enhanced toms. However, Calne et al15 did not find a consis-
antiparkinsonian effect.8 tent response in any patient with a low dosage. The
Most dopamine agonists are natural or synthetic incidence of adverse effects with bromocriptine
derivatives of ergot alkaloids. Many have been monotherapy in previously untreated Parkinson's
tested, but only bromocriptine and pergolide are disease is low. 16,17 Although bromocriptine mono-
currently available in United States (Table 1). In therapy may initially be as effective as levodopa,
patients with newly diagnosed Parkinson's disease, after 6 months levodopa is more effective.18 How-
monotherapy with bromocriptine or pergolide may ever, bromocriptine monotherapy is less likely to
initially provide symptomatic benefit comparable cause motor fluctuations and dyskinesia than is
to that of levodopa.9,10 However, over time, levo- levodopa monotherapy.15"19
dopa is usually required for an adequate antiparkin-
sonian effect.11 Most clinicians believe the role of Bromocriptine plus levodopa
dopamine agonists is as an adjuvant to levodopa in early Parkinson's disease
rather than as monotherapy. Mindful of these results, some clinicians recom-
mend early combination therapy with levodopa and
BROMOCRIPTINE bromocriptine to improve efficacy and to delay
long-term motor complications.12,20"23 In a study re-
Bromocriptine is an ergot alkaloid with potent ported by Rinne,20 patients found to have Parkin-
D2 agonist properties and a mild D1 receptor an- son's disease began taking levodopa; if they sub-
tagonistic effect. It is rapidly absorbed from the sequently had residual disability, bromocriptine was
gastrointestinal tract, 94% undergoes first-pass he- added while the levodopa dosage was kept the same.
patic metabolism, and only 6% of the original dose This combination was as effective as levodopa
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TABLE 2 in Parkinson's disease patients who have motor fluc-
COMMON ADVERSE EFFECTS OF DOPAMINE AGONISTS tuations and dyskinesia. Lieberman et al32 gave bro-
mocriptine to 66 patients who had advanced Park-
Nervous system complaints inson's disease and who were taking optimal
Dyskinesia levodopa dosages. In 45 patients, rigidity, tremor,
Hallucinations
Somnolence bradykinesia, postural stability, and gait improved
Insomnia significantly. The mean bromocriptine dosage was
Confusion
Digestive complaints 47 mg per day, and the investigators were able to
Nausea decrease the dosage of levodopa by 10%. However,
Constipation bromocriptine was discontinued in 29 patients be-
Diarrhea
Dyspepsia cause of adverse effects, including mental changes
Respiratory complaints and increased dyskinesia. Follow-up of 28 of these
Rhinitis patients for at least 2 years revealed that bro-
Other complaints
Dizziness mocriptine at a mean dosage of 56 mg per day re-
Orthostatic hypotension sulted in improvement in 75% of them.33 Sixteen of
the patients maintained improvement after 2 years.
Other studies have reported similar findings.34,35
alone, but produced less dyskinesia and motor fluc- However, in most of the long-term studies, the
tuation. These benefits persisted for 5 years.22 How- beneficial effects of bromocriptine waned over
ever, this study was open-label and nonrandomized, time.12 Although the exact mechanism is unknown,
and used historically matched controls. In the 5- disease progression or changes in dopamine recep-
year follow-up,22 Rinne included only patients tors may be responsible.
whose condition was stable enough to allow them to
remain in the study. Adverse effects of bromocriptine
Other studies support these findings12,20,23,24; how- One of the main drawbacks of dopamine agonists
ever, Weiner et al25 have raised several issues re- is frequent side effects (Table 2), many of which are
garding the conclusions. In a 4-year, double-blind, caused by dopaminergic stimulation. Starting
randomized, parallel-group trial comparing bro- dopamine agonists at a low dosage and slowly titrat-
mocriptine and levodopa alone and in combina- ing upward minimizes this problem. Orthostatic hy-
tion, early combination therapy did not prevent or potension and gastrointestinal dysfunction occur
delay the onset of motor fluctuation or dyskinesia early in treatment. Approximately 33% of patients
in Parkinson's disease. Unfortunately, there were report orthostatic hypotension, lightheadedness, or
some limitations to this study.26"28 Another study syncope.12 Nausea and vomiting are reported in 20%
(open-label) also did not find any significant differ- to 30% of patients. Adverse effects related to central
ences between the two treatments.29 dopaminergic stimulation include confusion, hallu-
If dopamine agonists do decrease motor fluctua- cinations, depression, psychosis, and dyskinesia.36
tion and dyskinesia, it is because they provide steady These side effects are more common in patients with
dopaminergic stimulation at the postsynaptic recep- severe disease and in those with dementia. Mental
tors. Controlled-release levodopa preparations also changes occur in 30% of patients,36 dyskinesia in
provide steady stimulation and produce fewer long- about 40%. 37 Dyspnea may occur, caused by
term complications than do standard levodopa dopaminergic drugs or pulmonary fibrosis.38
preparations.30,31 Therefore, it is our practice to use Erythromelalgia, cardiac arrhythmias, angina, reacti-
controlled-release levodopa for initiating levodopa vation of peptic ulcer, dry mouth, headache, and
treatment. At present, early combination therapy nasal stuffiness are other adverse effects reported
appears to have no advantage over controlled-re- with bromocriptine.38
lease carbidopa-levodopa, and it is more expensive.
Further studies are required, however. PERGOLIDE
Bromocriptine in late Parkinson's disease Pergolide, a semisynthetic ergoline dopamine
Bromocriptine as an adjuvant to levodopa has agonist, is 10 times more potent than bro-
undergone both open-label and double-blind studies mocriptine. Its half-life is 12 to 24 hours,39 it reaches
214 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 62 • NUMBER 4
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a peak plasma concentration within 1 to 2 hours, mean disability score was 49 at baseline, 17 at 10
and a single dose is completely cleared within 7 weeks of pergolide therapy, and 31 after 2.4 years.
days.12 Fifty-five percent is excreted in the urine, 5% Similarly, the "on" time increased 117% after 10
is excreted in expired air, and the remaining 40% to weeks of therapy, and after 2.4 years it was still 63%
50% is excreted in the feces.39 Pergolide has an greater than at baseline. These long-term studies are
affinity for both D1 and D2 receptors and stimulates similar to those reported with bromocriptine.
striatal adenylate cyclase activity in the presence of
guanosine triphosphate (GTP). 40 Adverse effects of pergolide
The dosage-escalation schedule for pergolide ap- The adverse effects of pergolide are similar in fre-
pears more complicated than it really is. The main quency and type to those of bromocriptine.12 In clini-
aim is to increase the dosage slowly to avoid adverse cal trials involving approximately 1200 patients,
effects. We prefer to start with one 0.05-mg pergolide 27% discontinued pergolide because of adverse ef-
tablet per day and increase by one tablet every fourth fects.55 The most common side effects include dyski-
day, until the patient is receiving five 0.05-mg tablets nesia, nausea, dizziness, hallucinations, rhinitis, con-
(or one 0.25-mg tablet) three times a day. fusion, constipation, somnolence, orthostatic
hypotension, and insomnia. Pergolide can also cause
Pergolide as monotherapy electrocardiographic changes, palpitations,44,52,56 and
Pergolide has not been extensively studied as asymptomatic arrhythmias.57 New-onset, dose-re-
monotherapy in Parkinson's disease. Rinne41 found lated angina, probably due to vasospasm, has been
that pergolide at a mean dosage of 2.6 mg per day reported in a few patients.58 However, Tanner et al59
alleviated parkinsonian symptoms in 10 previously studied six patients who had Parkinson's disease and
untreated patients; however the degree of improve- stable heart disease and found no worsening of car-
ment was less than with levodopa alone. diac status during 1 year of therapy. There are no
contraindications to the use of pergolide in Parkin-
Pergolide as an adjuvant to levodopa son's disease patients with stable heart disease.
In several short-term studies (less than 3 months),
adding pergolide (0.1 to 15 mg per day) to levodopa W H I C H D O P A M I N E A G O N I S T T O USE
decreased disability, dyskinesia, and "off" time in pa-
tients with Parkinson's disease.42"45 Many patients Since two drugs are currently available with com-
were able to reduce their levodopa dosage,43,45 and a parable efficacy and action, which one should be
few were able to discontinue it altogether.42'44 used? Further, when should one be substituted for
Placebo-controlled studies have yielded similar the other?
findings. Olanow and Alberts46 reported that a mean In a double-blind crossover study in nine patients
pergolide dosage of 2.5 mg per day reduced levodopa with mild Parkinson's disease and 15 patients with
requirements by 33%, whereas Jankovic and Or- advanced disease, LeWitt et al60 found bro-
man47 reported that 4.6 mg per day reduced levodopa mocriptine and pergolide equivalent in efficacy and
requirements by 78%. This also resulted in a decrease adverse effects. In a retrospective study, Lieberman
in "off' time, disability, and disease severity. et al61 found pergolide more useful than bro-
There have been many long-term, open-label tri- mocriptine because of its efficacy at a more ad-
als of pergolide.48-54 Ahlskog and Muenter54 found vanced stage of the disease. In a 5-year study, Goetz
that patients who initially had a dramatic response et al62 gave 10 patients bromocriptine until its effi-
to pergolide were likely to show a sustained re- cacy waned and then changed their medication to
sponse. In a number of studies, the response to per- pergolide. Even though bromocriptine was losing its
golide peaked at 2 to 12 months48"53 and deteriorated effect, pergolide still produced a response, and re-
slowly thereafter.48'49,51 Lieberman et al51 treated 17 mained effective longer than bromocriptine. In a
patients with pergolide for more than 2 years. At a similar study,63 the investigators switched the regi-
mean dosage of 2.2 mg per day, there was a 20% men from pergolide to bromocriptine, and the pa-
reduction in disability and a 40% increase in "on" tients continued to do well clinically.
time compared with baseline; however, none of These studies provide little guidance regarding
these changes reached statistical significance. Jank- which drug to use. However, bromocriptine is about
ovic53 reported his experience with 18 patients; the twice as expensive as pergolide in an equivalent
JULY • AUGUST 1995 CLEVELAND CLINIC JOURNAL OF MEDICINE 215
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dose. For this reason, we use pergolide in preference or pergolide. Its plasma half-life is approximately 65
to bromocriptine in treating Parkinson's disease. hours,70,71 and it can be given once a day.
Pramipexole, a selective dopamine D2 agonist, has
therapeutic potential for use in schizophrenia and
may decrease the incidence of mental adverse ef-
Apomorphine and lisuride, dopamine agonists fects seen with dopamine agonists.72 Similarly, stud-
available in Europe, are lipophilic and soluble in ies with ropinirole indicate a lower incidence of
aqueous solution and can be given parenterally.12 gastrointestinal side effects and orthostatic hypo-
The subcutaneous route is most commonly em- tension.73
ployed, with subcutaneous infusions given via bat-
tery-powered ambulatory pumps.64-66 Apomorphine
is also effective when used sublingually,67 in-
tranasally,68 and rectally.69 The role of dopamine agonists in treating Parkin-
Cabergoline, pramipexole, and ropinirole are son's disease has not yet been fully worked out, but
dopamine agonists presently undergoing clinical most clinicians feel they are best used as adjuvants
trials in the United States. Cabergoline, a synthetic to levodopa therapy. Used in this way, these drugs
dopaminergic agonist specific for the D2 receptor, is can produce clinical improvement and can often
more potent and longer-acting than bromocriptine permit a lowering of the levodopa dosage.
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