Pergolide versus levodopa monotherapy in early Parkinson's disease patients: The PELMOPET study.

Dopamine agonists are used as initial treatment in patients with Parkinson's disease (PD) to reduce incidence and severity of motor complications. This paradigm is based on long-term studies, allowing "rescue" therapy with levodopa. The present strict monotherapy study (PELMOPET, the acronym for the pergolide-versus-L-dopa-monotherapy-and-positron-emission-tomography trial) evaluated the efficacy and safety of pergolide versus levodopa without levodopa "rescue" medication. This multicenter, double-blind, randomized, 3-year trial compared pergolide monotherapy (n=148) with levodopa monotherapy (n=146) in dopamine-naive patients with early PD (Hoehn and Yahr stage 1-2.5). Primary efficacy measures were clinical efficacy, severity and time to onset of motor complications, and disease progression. During the 3 years, severity of motor complications was significantly lower and time to onset of dyskinesia was significantly delayed in the group receiving pergolide (3.23 mg/day) compared with those receiving levodopa (504 mg/day). However, time to onset of motor complications was not longer in patients receiving pergolide after 3 years. Symptomatic relief (assessed by Unified Parkinson's Disease Rating Scale [UPDRS], UPDRS II, and III, Clinical Global Impressions [CGI] severity, and CGI and Patient Global Impressions [PGI] improvement) was significantly greater in patients receiving levodopa. Adverse events led to discontinuation of therapy in 17.6% of pergolide patients and 9.6% of levodopa patients. This is the first study comparing strict monotherapy with a dopamine agonist versus levodopa in previously untreated early PD. In principle, both levodopa and a dopamine agonist such as pergolide seem to be suitable options as initial PD therapy. The choice remains with the treating physician based on the different efficacy and adverse event profiles.     

Dopamine agonists, receptor selectivity and dyskinesia induction in Parkinson's disease

Levodopa and the dopamine agonists are effective symptomatic treatments for Parkinson's disease, and all patients receive at least one of these agents during their illness. Long-term use of levodopa is commonly associated with motor complications such as dyskinesia, and both the dosing frequency and total daily dose of levodopa determine the rate of onset and severity. Dopamine agonists have gained popularity as first-line monotherapy in Parkinson's disease, as they effectively reverse motor deficits and reduce the risk of motor complications. Long-acting dopamine agonists providing continuous, rather than pulsatile, dopaminergic stimulation appear able to avoid dyskinesia induction. Current treatments act predominantly on D2 receptors, but drugs acting on both the D1 and D2 receptor families may produce an additive motor response, although this remains to be proven in patients with Parkinson's disease. Most currently used dopamine agonists are selective for D2-like receptors, with only pergolide and apomorphine potentially interacting with D1 receptor populations.     

Dopamine agonists in Parkinson's disease

Dopamine agonists are established as effective drugs for the symptomatic treatment of Parkinson's disease (PD) throughout its course. As monotherapy, they produce effective control of motor symptoms and combine this with a low risk for motor complications. As an adjunct to levodopa, they improve motor control and limit the need for levodopa in those patients in whom this may be considered relevant. The non-ergot dopamine agonists in particular have a good safety profile, although as with other agonists, sedation, and cognitive and behavioral problems may be limiting in some patients. Pramipexole has shown benefit in improving depressive symptoms in PD. Ropinirole and pramipexole have both demonstrated a reduction in the rate of loss of nigrostriatal innervation as determined by imaging in PD patients, when compared with levodopa. Thus, dopamine agonists contribute to several dimensions of the management of PD and have become an integral part of the disease treatment algorithm.     

Levodopa or dopamine agonists, or deprenyl as initial treatment for Parkinson's disease. A randomized multicenter study

Objectives: levodopa improves the quality of life in parkinsonian patients, however long term response is compromised by the emergence of motor fluctuations and dyskinesias. The aim of this study was to compare the occurrence of motor fluctuations and dyskinesias in previously untreated patients assigned to receive levodopa, a dopamine agonist or deprenyl.Thirty-five neurological departments in Italian hospitals participated in this randomized open trial. Patients with Parkinson's disease, who required the initiation of an effective antiparkinsonian treatment, were randomly assigned to receive levodopa, dopamine agonists or deprenyl. The end-points were motor dyskinesias and motor fluctuations occurring in a median follow-up period of about 3years.After a median follow-up of 34months, motor fluctuations and dyskinesias were less frequent in patients assigned to a dopamine agonist or deprenyl than in patients assigned to levodopa (relative risk [RR] 0.5, 95% confidence interval [95% CI] 0.3-0.8, and RR=0.6, 95% CI 0.3-0.9, respectively), but dopamine agonists were less effective and less well tolerated than levodopa. The lower frequency of motor fluctuations in patients assigned to deprenyl was no longer statistically significant when prognostic predictors were considered in a multivariable analysis. Long-term mortality did not differ in the three arms of the study. Dopamine agonists and deprenyl can be considered as an alternative to levodopa for starting treatment in Parkinson's disease patients. However, on clinical grounds, only small advantages are expected over the traditional therapy initiation with levodopa.     

Pergolide in the treatment of patients with early and advanced Parkinson's disease

Introduced on the market in 1989, pergolide, a D1/D2 dopamine receptor agonist, is still widely prescribed for the treatment of patients with early and advanced Parkinson's disease (PD). Initially, pergolide was introduced as an adjunct therapy to levodopa treatment in patients exhibiting fluctuating motor responses and dyskinesias. Results of recent randomized controlled clinical trials in de novo patients with PD show that pergolide is able to improve parkinsonian symptoms when used as monotherapy. Moreover, preliminary results of a long-term monotherapy study in early PD suggest that pergolide is as effective as levodopa, and that a significant delay in the time of the onset of levodopa-induced motor complications can be obtained. A number of randomized studies have shown that pergolide is more effective than bromocriptine as adjunct therapy to levodopa in patients with advanced PD; the greater benefit found with pergolide could be ascribed to its action on both D1 and D2 dopamine receptors. However, controlled comparative studies with new dopamine agonists, such as ropinirole, cabergoline, and pramipexole, have not been performed yet. Interestingly, few open studies in patients with complicated PD have shown that high doses of pergolide (> 6 mg/d) are able to improve motor fluctuations and dyskinesias through a dramatic reduction of levodopa dosage. The side-effect profile of pergolide is similar to that of other dopamine agonists, and complications such as sleep attack and serosal fibrosis have been rarely reported.     

Dopamine agonists: the treatment for Parkinson's disease in the XXI century?

Levodopa combined with a peripheral dopa-decarboxylase inhibitor (DCI) has been considered the therapy of choice for Parkinson's disease (PD). Levodopa is nearly always effective, but has a high incidence of adverse effects with long term use, including response fluctuations (on/off phenomena) and dyskinesias. Dopaminergic agonists, acting directly at the receptor level, would be able to decrease the incidence of these motor complications.In progressive neurodegenerative diseases, such as PD, modification of the rate of disease progression (often referred to as neuroprotection) is currently a highly debated topic. Increased oxidative stress is thought to be involved in nigral cell death, that is characteristic of PD. This oxidative stress may be further exacerbated by levodopa therapy. These mechanisms have been proven in vitro and animal models, but it's relevance in humans remains speculative.Based on the considerations above, the emerging therapeutic strategies for PD advocate early use of dopamine agonists in the treatment of PD. A number of recent well-controlled studies have proven the efficacy of dopamine agonists used as monotherapy. Moreover, as predicted by animal studies, on the long term, dopaminergic agonists induce significantly less motor complications than levodopa.In the last 2years, three new dopamine agonists have been launched, including ropinirole, pramipexole and cabergoline. These new agonists have been added, as therapeutical options to well-established drugs, like pergolide, bromocriptine or talipexole. The recently launched compounds have proven efficacy in monotherapy and as adjunctive therapy to levodopa. Unfortunately, only a very limited amount of comparative data among the different agonists is available. Pergolide has proven to be a superior drug to bromocriptine as adjunctive therapy to levodopa in a significant number of studies and is considered the gold standard dopamine agonist. Nevertheless, none of the recently launched compounds has compared itself against pergolide.A comparison of monotherapy trials is difficult, because of differences in design and populations. In a recently completed trial pergolide was statistically significantly better than placebo in all the efficacy parameters tested, with 57% of pergolide treated patients improving over 30% in the motor section of the UPDRS, as compared to 17% in the placebo arm. Interestingly, these results were obtained in the absence of any other antiparkinsonian drug during the trial. Recent monotherapy trials done with ropinirole and pramipexole achieved also significant improvements as monotherapy, but in these cases selegeline, a drug that causes a symptomatic improvement in PD, was allowed as co-medications during the trial. Not all trials used the same efficacy measures, i.e. monotherapy trials with pergolide and ropinirole used a "responder" based analysis (responder were all patients that improved 30% or more on the motor section of UPDRS), as well as a baseline to endpoint improvement in motor scores. Pramipexole monotherapy trials used only the latter approach, which is clinically less powerful than a responder analysis.Even with the difficulties mentioned above, all the recent trials with dopamine agonists have proven that these drugs are a useful symptomatic long term treatment for PD with or without levodopa and that the early use of dopamine agonists reduces the incidence of motor complications as compared to levodopa.     

Treatment of Parkinson''s disease

The aim of current treatment of Parkinson's disease is to ameliorate the symptoms while seeking to lessen the potential development of late levodopa complications. To this end, there is ample evidence that the early use of dopamine agonists is beneficial in younger Parkinsonian patients but monotherapy with dopamine agonists is for only a select few. Nonergot dopamine agonists offer the potential for fewer side effects. Lower dose levodopa therapy delays the onset and reduces severity of dyskinesia and end of dose failure. However levodopa remains the treatment of choice in Parkinson's disease and should not be restricted unnecessarily in patients with disability. There is no evidence that levodopa is toxic to dopaminergic neurons in people with Parkinson's disease. As yet, no drugs are of proven neuroprotective value. Dopamine agonists, catechol-o-methyltransferase inhibitors, amantadine and apomorphine have differing but beneficial roles in the management of levodopa side effects. Ablative surgery and deep brain stimulation of thalamus, globus pallidus and subthalamic nucleus are increasingly available but choice of procedure depends not just on patient symptomatology, but also on local experience and results. Ideally, deep brain stimulation is the treatment of choice as it offers less morbidity than bilateral ablative surgery, the possibility of postoperative adjustments and the potential for reversibility if better treatments become available.     

A reassessment of risks and benefits of dopamine agonists in Parkinson's disease

Neurologists have several choices of drugs that have been shown to be effective for the treatment of the symptoms of Parkinson's disease. Among the first options are the dopamine agonists, which are commonly used both as an early monotherapy and as an adjunct therapy to levodopa. However, before starting any treatment, the overall benefit-to-risk ratio to individual patients must be considered. For the dopamine agonists, the available evidence on their symptomatic efficacy, effect on long-term levodopa-related motor complications, putative effect on progression of disease, and adverse event profile must be taken into account. Recently, the ocurrence of adverse events such as leg oedema, daytime somnolence, impulse control disorders, and fibrosis have increasingly been recognised. The risks of these potentially serious adverse events must therefore be taken into account and treatment decisions should be based on considerations of risks versus benefits for individual patients.     

Dopamine agonists in the treatment of early Parkinson's disease: a meta-analysis

Our objective was to perform a meta-analysis of randomized controlled trials of dopamine agonists (DA) as monotherapy as well as adjunctive therapy for the early treatment of Parkinson's disease (PD). A systematic literature search was conducted through April 2007. Both efficacy and safety endpoints were evaluated. DA monotherapy showed superior efficacy but more frequent adverse events compared to placebo. In addition, DA demonstrated inferior efficacy to levodopa, but was associated with fewer motor complications. However, DAs were associated with a greater incidence of nuisance side effects, such as hallucinations, somnolence and dizziness. The use of DA is an effective treatment option for the treatment of early PD and appears especially useful among PD patients with wearing-off phenomenon or dyskinesias on levodopa; however it may result in more adverse events and higher withdrawal rates.     

Treatment of Parkinson's disease should begin with a dopamine agonist.

The occurrence of side effects with long-term levodopa therapy, such as fluctuations in motor performance or abnormal movements, led to a search for new antiparkinsonian drugs. Dopamine agonists include ergot derivatives such as bromocriptine, lisuride, pergolide, and cabergoline and other agents which do not possess the ergot structure such as pramipexole and ropinirole. They all are powerful stimulators of the D2 dopamine receptor which probably underlies their therapeutic effects. The clinical consequences of their binding to other dopamine receptor subtypes (D1 or D3) remains unknown. They are usually prescribed in combination with levodopa when late side effects begin to occur. This review summarizes the available pharmacologic and clinical data to support the early use of dopamine agonists in Parkinson's disease. Several strategies can be used, such as monotherapy or "early" or "late" combination with levodopa. Results of recent well-performed, modern clinical trials show that early use of the new dopamine agonists is able to effectively control the clinical symptoms for more than 3 years thereby offering the possibility of delaying the occurrence of levodopa-induced late motor side effects.     

Initial therapy for Parkinson's disease: levodopa vs. dopamine receptor agonists

Levodopa therapy is essential for patients in the advanced stages of Parkinson's disease. However, at early stages, DA agonist therapy has similar efficacy in the treatment of parkinsonism and a lower incidence of motor complications compared to levodopa therapy several years after the initiation of the therapy. The main factors causing motor complications have been speculated to be a severe reduction of dopaminergic nerve terminals because of disease progression, and a pulsatile stimulation of DA receptors using a drug with a short plasma half-life. DA agonists have longer plasma half-lifes than levodopa; therefore, they are expected to have a favorable effect on motor complications. Moreover, two clinical reports confirmed the potential neuroprotection by DA agonists. Although the patient's conditions should be considered in the selsction of a drug, DA agonist therapy is recommended as the initial therapy for Parkinson's disease.     

Pulsatile or continuous dopaminomimetic strategies in Parkinson's disease

Levodopa is the most effective treatment for Parkinson's disease (PD) for both motor and non-motor control. Pulsatile levodopa administration likely contributes to the development of motor fluctuations and dyskinesia after a few years. All studies comparing levodopa versus dopamine agonist early therapy indicate that initiation with agonists is associated with a reduced risk of motor complications - in particular, dyskinesias - possibly because agonists' longer half-lives provide continuous dopaminergic delivery. Indeed, this therapeutic strategy may delay the emergence of motor fluctuations and dyskinesia which is essential to maintaining satisfactory quality of life. In advanced disease various levodopa-based strategies may be tried to control motor complications, such as dose fragmentation (smaller, more frequent dosing) or the use of orally administered, liquid levodopa formulations that may reduce off-time intervals or facilitate absorption. More recently introduced, continuous levodopa delivery by duodenal infusion (but also apomorphine infusion) may represent a more effective approach to treat motor complications in advanced PD, and its effect can be perceived by improvement both in clinical scales as well as in health-related items. Infusion therapies may reverse motor complications in complicated patients with significant benefit on quality of life.     

Erste doppelblinde Langzeitstudie zum Nachweis der Wirksamkeit und Dyskinesieprophylaxe von Ropinirol

Psychiatric symptoms and motor fluctuations are frequently occurring late sequelae of long-term therapy with L-dopa. Up to 80% of patients on L-dopa therapy suffer from disturbing dyskinesias, with onset during the first few years after beginning treatment. In particular, younger and middle-aged patients with idiopathic parkinsonian syndrome may develop dyskinesias in the early years of L-dopa therapy. We propose that these particular patient groups should initially be treated with a dopamine agonist--if possible in monotherapy but at least in a dopamine agonist-dominated combination therapy with L-dopa. In this paper, we discuss the reasons for these recommendations, which are based on the findings of the first double-blinded study in which L-dopa was compared with ropinirole, a nonergot dopamine agonist, over a 5-year period. The main results of this study are as follows: At least 1/3 of patients in the ropinirole group could be treated with the dopamine agonist in monotherapy over 5 years. Treatment in the ropinirole group was as effective as in the L-dopa group. Despite equal effectiveness of both drugs, the incidence of dyskinesias was considerably lower with ropinirole (5%) than with L-dopa (36%). The long-term experience gained in this 5-year study support our recommendations to use dopamine agonists early and as the preferred drug of choice in the treatment of Parkinson's disease.     

Medication treatment for Parkinson's disease

In general, therapy for Parkinson's disease is dominated by dopamine agonists (DA) in younger patients and levodopa in older patients with comorbidities. Single or combined treatment with DA should be used as long as possible to avoid levodopa and associated complications. About 30% of our patients respond to DA monotherapy and tolerate it for quite a long time. It is important to sustain patient confidence. Although parkinsonism is an insidious disease of unknown cause resulting in destruction of important dopaminergic neurons, no other neurodegenerative disease can be treated as successfully.     

Treatment of Parkinson's disease

Parkinson's disease is a progressive neurodegenerative disorder that demands a holistic approach to treatment. Both pharmacologic and nonpharmacologic interventions play an important role in the comprehensive management of this disorder. While levodopa remains the single most effective medication for symptomatic treatment, dopamine agonists are playing an increasingly important role. Motor complications of dopaminergic therapy are a significant issue, particularly in patients with more advanced disease who have been on levodopa for several years. All therapeutic interventions must be tailored to the individual and modified as the disease progresses, with the goal of minimizing significant functional disability as much as possible.     

Treatment of Parkinson's disease: Problems with a progressing disease

Summary Long-term follow-up of parkinsonian patients has shown that although levodopa treatment significantly improves the parkinsonian symptoms and the quality of life of parkinsonian patients for several years, various distressing difficulties arise during chronic levodopa treatment, such as the loss of benefit, dyskinesias, on-off phenomena, postural instability and dementia. Clinical, neuropsychological, mortality and post-mortem brain studies indicate that levodopa as a replacement therapy does not modify the progression of the underlying pathology and the natural course of the disease. It seems that levodopa has only a limited period of optimal usefulness in the treatment of Parkinson's disease. However, at present there is no better or more potent therapeutic agent available than levodopa and it is still the primary treatment of Parkinson's disease. It would be reasonable not to begin levodopa treatment in patients with mild symptoms but to withold levodopa until the severity of symptoms really makes its use necessary. Thus it is possible to get the maximal long functional benefit.Post-mortem brain studies have shown that in Parkinson's disease there is not only a progressive loss of dopaminergic substantia nigra neurons but there are also significant changes in the striatal dopamine receptors. In some patients a denervation supersensitivity seems to develop and in some others a loss of dopamine receptors in the striatum. However, in advanced parkinsonian patients with a deteriorating response to levodopa, there seem to be still enough dopamine receptors in the striatum for drugs stimulating the dopamine receptors directly to improve the parkinsonian disability. Indeed, recent evidence indicates that dopaminergic agonists, such as bromocriptine, seem to be a significant and valuable adjuvant therapy to levodopa in parkinsonian patients with a deteriorating response and/or the on-off phenomena. Although bromocriptine is not completely satisfactory, it is a significant opening to a new mode of treatment. In the future it will be very important to develop more potent and selective dopaminergic agonists affecting only those striatal receptors which are mainly responsible for the parkinsonian symptoms. Then a better therapeutic response is likely to occur and many central side effects can be avoided.Current difficulties in the management of Parkinson's disease greatly depend on the fact that we are dealing with a symptomatic therapy. It is hoped that future research will soon lead to a discovery of the primary cause and consequently to a causal therapy of Parkinson's disease.     

Rationale for dopamine agonist use as monotherapy in Parkinson's disease

Dopamine agonists are increasingly being used in the initial treatment of patients with de-novo Parkinson's disease because they provide symptom relief and a low risk of the dyskinesia frequently associated with levodopa. Evidence is also mounting in preclinical models that dopamine agonists protect dopaminergic neurons from the toxic effects of oxidative stress and the by-products of dopamine and L-dopa metabolism. Ergot derivatives, such as pergolide, induce minor side-effects and provide significant and sustained improvements in motor function in patients with early Parkinson's disease. Dopamine agonists also appear to reduce the loss of functional dopamine transporters when used early in the disease course, and these factors combine to build a case for the use of dopamine agonists in early-stage Parkinson's disease.     

Neuroprotection and pharmacotherapy for motor symptoms in Parkinson's disease

Parkinson's disease leads to major disability that impairs the quality of life of patients and leads to increased health-care costs. While there is no proven neuroprotective treatment, more basic-science research and clinical trials are needed to identify drugs that slow or halt the progression of the disorder. The mainstay of symptomatic treatment is levodopa. With long-term use, levodopa causes motor complications including involuntary movements and response fluctuations. These have lead to more cautious prescribing of levodopa. Dopamine agonists can be used as an alternative initial therapy to delay the onset of motor complications but at the expense of more dopaminergic adverse events, poorer control of motor symptoms, and increased cost. Once motor complications have developed, adjuvant therapy with dopamine agonists or entacapone can reduce off time and levodopa dose. Severe fluctuations that are not controlled by oral combination therapy can be controlled with subcutaneous apomorphine injections or infusions.     

Apomorphine: an underutilized therapy for Parkinson's disease.

Apomorphine was the first dopaminergic drug ever used to treat symptoms of Parkinson's disease. While powerful antiparkinsonian effects had been observed as early as 1951, the potential of treating fluctuating Parkinson's disease by subcutaneous administration of apomorphine has only recently become the subject of systematic study. A number of small scale clinical trials have unequivocally shown that intermittent subcutaneous apomorphine injections produce antiparkinsonian benefit close if not identical to that seen with levodopa and that apomorphine rescue injections can reliably revert off-periods even in patients with complex on-off motor swings. Continuous subcutaneous apomorphine infusions can reduce daily off-time by more than 50% in this group of patients, which appears to be a stronger effect than that generally seen with add-on therapy with oral dopamine agonists or COMT inhibitors. Extended follow-up studies of up to 8 years have demonstrated long-term persistence of apomorphine efficacy. In addition, there is convincing clinical evidence that monotherapy with continuous subcutaneous apomorphine infusions is associated with marked reductions of preexisting levodopa-induced dyskinesias. The main side effects of subcutaneous apomorphine treatment are related to cutaneous tolerability problems, whereas sedation and psychiatric complications play a lesser role. Given the marked degree of efficacy of subcutaneous apomorphine treatment in fluctuating Parkinson's disease, this approach seems to deserve more widespread clinical use.     

Rotigotine for the treatment of Parkinson's disease

Dopaminergic therapies, including levodopa and dopamine agonists, are the mainstays of therapy in Parkinson's disease. With the exception of the injectable short-acting dopamine agonist apomorphine, there is no other widely available non-oral dopaminergic therapy. Rotigotine is a lipid-soluble, non-ergot, D3, D2, D1 dopamine receptor agonist that has demonstrated efficacy as an alternative therapeutic option in both early and advanced Parkinson's disease. More importantly, it is uniquely formulated as a transdermal patch delivery system allowing for continuous, once-daily administration and better patient compliance. Preclinical and clinical trials have shown rotigotine to be a well-tolerated and effective treatment for early-stage Parkinson's disease. Rotigotine has also shown promise as adjunctive therapy with levodopa for the treatment of advanced Parkinson's disease.