Abstract
Parkinson’s disease is a chronic degenerative organic disease with unknown causes. A disappearance of cells with melanin in the substantia nigra is considered as biological artefact of the disease, which causes a degenerative loss of neurons in the corpus striatum of mesencephalon. This structure produces also the transmitter substance dopamine. Due to this disappearance of cells dopamine is not produced in a sufficient quantity which is needed for movement of the body.
The questions of this report are concerned the efficiency and safety of a treatment with dopamine agonists. Furthermore the cost-effectiveness is investigated as well as ethic questions. The goal is to give recommendation for the use of dopamine agonists to the German health system.
A systematic literature search was done. The identified studies have different methodological quality and investigate different hypothesis and different outcome criteria. Therefore a qualitative method of information synthesis was chosen.
Since the introduction of L-Dopa in the 1960´s it is considered as the most effective substance to reduce all the cardinal symptoms of Parkinson disease. This substance was improved in the course of time. Firstly some additional substances were given (decarbonxylase inhibitors, catechol-o-transferase inhibitors (COMT-inhibitors), monoaminoxydase-inhibitors (MAO-inhibitors) and NMDA-antagonists (N-Methyl-d-aspartat-antagonists).
In the practical therapy of Parkinson dopamine agonists play an important role, because they directly use the dopamine receptors. The monotherapy of Parkinson disease is basically possible and is used in early stages of the disease. Clinical practise has shown, that an add on therapy with dopamine agonists can led to a reduction of the dose of L-dopa and a reduction of following dyskinesia.
The studies for effectiveness include studies for the initial therapy, monotherapy and add-on-therapy. Basically there is a good effectiveness of dopamine agonists the reduce dyskinesia and this differences are statistically significant. The effect of dopamine agonists is weaker then levodopa generally. The initial therapy with dopamine agonists can postpone the use of levodopa medication or keep the dose small for a longer period of time. There are more other side effects to levodopa, these are not statistically significant.
The idea, which strategy for the treatment should be chosen is dependent of several factors and has to be evaluated with the individual patient. An important criterion is the age of the patient at the beginning of the treatment. For younger patients (under 65 years) the risk of developing motoric fluctuation and dyskinesia is much higher and therefore it is proposed to use levodopa at later stages. The evidence of the evaluated studies show a good effectiveness with the therapy of Parkinson disease as monotherapy of younger patients or as additional medication to levodopa as well as older patients with progressive stages of this disease. In these groups of patients there is a positive cost-benefit ratio.
Abstract
Die Parkinsonkrankheit ist ein chronisch-fortschreitendes organisches Nervenleiden, dessen Ursachen noch unbekannt sind. Ein Untergang von melaninhaltigen Zellen in der Substantia nigra führt zum Zellverlust im „Corpus Striatum“. Die klinische Symptomatik des Morbus Parkinson besteht hauptsächlich in Bewegungsverarmung (Bradykinese), Tremor (Schüttelbewegungen) und Rigor (zäher Widerstand der Muskulatur).
Die Fragestellungen der vorliegenden Arbeit betreffen vor allem die Wirksamkeit und Sicherheit der Behandlung mit Dopaminagonisten, außerdem soll nach der Kosten-Nutzen-Effizienz gefragt werden und ethische Überlegungen zur Behandlung des Parkinsonsyndroms mit Dopaminagonisten angestellt werden. Ziel ist, dem deutschen Gesundheitssystem Empfehlungen zum Umgang mit Dopaminagonisten zu geben.
Es fand eine systematische Literaturrecherche in allen relevanten medizinischen Literaturdatenbanken statt. Die gefundenen Studien sind unterschiedlicher methodischer Qualität und verwenden unterschiedliche inhaltliche Fragestellungen und Outcomeparameter. Deshalb wurde auf qualitative Syntheseverfahren zurückgegriffen.
Seit ihrer Einführung in den 60-er Jahren gilt Levodopa (L-Dopa) als die wirksamste Parkinsontherapie, die alle Kardinalsymptome der Erkrankung zurückdrängen hilft, die seither laufend verbessert wurde. Zunächst wurden verschiedene Medikamente zusätzlich zu L-Dopa verabreicht. Dazu zählen Decarboxylasehemmer, Catechol-O-Transferasehemmer (COMT-Hemmer), Monoaminoxydasehemmer (MAO-Hemmer), und NMDA-Antagonisten (N-Methyl-D-Aspartat-Antagonisten).
In der praktischen Therapie der Parkinsonerkrankung spielen die Dopaminagonisten eine große Rolle, da sie direkt an den Dopaminrezeptoren angreifen. Eine Monotherapie der Parkinsonerkrankung mit Dopaminagonisten ist prinzipiell möglich und wird zumeist neu diagnostizierten (de-novo) Patienten verabreicht. Später kommt zumeist L-Dopa hinzu. Die klinische Praxis hat gezeigt, dass eine „Add-On“-Therapie (Adjuvante Therapie) mit Dopaminagonisten eine L-Dopa Dosisverringerung und eine Verringerung bereits bestehender Dyskinesien bewirken kann.
Die Studien zur Wirksamkeit der ergoten Dopaminagonisten beinhalten Studien zur Initial- bzw. Monotherapie an de-novo Patienten und „Add-On“-Therapie bei fortgeschrittener Parkinsonerkankung und bei Motorfluktuationen. Grundsätzlich wird über eine gute Wirksamkeit der Dopaminagonisten auf Dyskinesien berichtet, wobei signifikante Unterschiede zu Placebo erzielt wurden. Die Wirksamkeit der Dopaminagonisten auf die Symptomatik im Allgemeinen ist schwächer als bei Levodopa. Eine Initialtherapie mit Dopaminagonisten kann den Beginn der L-Dopa-Medikation hinauszögern und die Dosierungen lange Zeit niedrig halten. Es zeigen sich mehr Nebenwirkungen als unter L-Dopa, jedoch sind dies keine signifikanten Unterschiede.
Die Überlegung, welche Therapiestrategie bei Parkinsonpatienten verfolgt werden sollte, hängt von mehreren Faktoren ab und muss dem individuellen Einzelfall angepasst werden. Eine wichtige Überlegung spielt das Alter der Patienten zu Beginn der Erkrankung. Bei jüngeren Patienten (zumeist unter 65 Jahren) liegt das Risiko für die Entwicklung von motorischen Fluktuationen und Dyskinesien wesentlich höher und daher wird versucht, L-Dopa erst später einzusetzen. Die Evidenz in der bewerteten Literatur zum Thema der Dopaminagonisten zur Behandlung des Parkinsonsyndroms weist auf eine gute Wirksamkeit bei Anwendung als Monotherapie von jüngeren Parkinsonpatienten, oder als zusätzlichen Gabe zu L-Dopa, bei älteren Patienten in fortgeschritteneren Stadien der Erkrankung hin. Bei einer solchen Anwendung ist auch ein positives Kosten-Nutzen-Verhältnis gegeben.
Executive Summary
1. Health political background
Parkinson’s disease is a chronic neurodegenerative disease which frequency increases whose causes are unknown and whose therapies partly are connected to a clear reduction of the quality of life. This disease is well known in the society. Patients are easily recognized and in the case of no adequate therapy they suffer of social isolation. Illnesses within the age of active working are not rare.
Miscellaneous therapy approaches which considerably show different effects, side effects as well as costs exist. Each patient has to be considered individually, but the decision for a treatment is an evaluation of a more cost intensive therapy, improve of quality of life and a possible delay for severe stages for the disease.
There is the political question, whether the need for additional financial expenditure can be compensated by a delay of the disease, reduced hospital costs of costs for nursing.
What can a health politician do to improve the problem of these patients? Is it just to pay more for the patients? Is there a general social advantage which can be achieved?
From the scientific point of view there are many hints that the dopamine agonists – the more expensive class of substances is worth to be paid because reductions of costs in the field of long-term-care or an early stop of working can be postponed.
These facts should be brought to a detailed health economic evaluation since these individual indications from international studies are not transferable directly to the German health system with such a certainty, which is necessary for real political decisions.
2. Introduction
Parkinson’s disease is a chronic degenerative organic disease which cause is unknown. A disappearance of cells with melanin in the substantia nigra is considered as biological artefact of the disease, which causes a degenerative loss of neurons in the corpus striatum of mesencephalon. This structure produces also the transmitter substance dopamine. Due to this disappearance of cells dopamine is not produced in a sufficient quantity which is needed for movement of the body.
The clinical symptoms of Parkinson’s disease is mainly the bradykinesis, tremor (especially one-sided in rest), and rigor (muscles tends to resistance at passive movement), and occurs when 50 to 60% of the cells disappeared and the lack of dopamine is about 80%.
This HTA-report will evaluate the effectiveness of dopamine agonists for the treatment of Parkinson’s disease.
3. Questions
Dopamine agonists are used regularly for Parkinson’s disease. This report tries to answer the following questions:
What about the effectiveness and safety of dopamine agonists with the treatment of Parkinson’s disease?
What is the cost-efficiency of the therapy with dopamine agonists in comparison to other therapies?
Are there ethical considerations important when this therapy is used?
Which recommendations can be given for the German health care system for the use of dopamine agonists?
4. Methods
A systematic literature search was done in all relevant literature databases. The identified literature was examined by two independent reviewers and analysed for this report. The method for information synthesis should be quantified as much as possible which was difficult due to the bad direct comparison of the studies and the frequent lack of quality of the studies in the sense of evidence based medicine. Therefore qualitative methods of information synthesis were used.
5. Background of the disease
About 250,000 people suffer on Parkinson’s disease in Germany. Another 100,000 can be assumed as not detected. Up to 180 patients per 100,000 habitants are estimated. About 1% of the 60-years old people and 3% of the 80-years old people have Parkinson’s disease. 10% of the patients are younger than 40 years, 30% younger than 50 years. 40% get the disease between 50 and 60 years. Men have a double risk to get the disease then women. Incidence is increasing with age.
The clinical symptoms or Morbus Parkinson is mainly the bradykinesis, tremor (especially one-sided in rest), and rigor (muscles goes in resistance to passive move, when 50 to 60% of the cells disappeared and the lack of dopamine is about 80%).
6. Diagnostic methods
An important method for the evaluation of the functionality is the UPDRS (Unified Parkinson’s Disease Rating Scale) especially the part II “Activities of daily living”, which comprehend an evaluation of the most important activities of a person, like talking, swallowing, writing, cutting food, practibility, hygiene, turn in bed, falling, walking, tremor and recognition.
Some procedures are necessary for testing the loss of dopamine neurons in the nigrostratial region. That is the PET (positron emission tomography) which needs the 6-florotopa marker.
An alternative method is SPECT (Single Photon emission tomography). The representation is done with the use of the ligand 123J-IPT or 123J-Beta-CIT, which can bind dopamine receptors. Postsynaptic dopamine receptos can be detected by 123J-IBZM. The loss of nerve ending in the corpus stratium can be detected by 123I-FP-CIT by a reduced density of dopamine-transporting proteins.
7. Dopamine agonists for treatment of Parkinson´s disease
7.1 Levodopa – the gold standard in the treatment of Morbus Parkinson
Since the introduction in the 1960´s L-Dopa (levodopa) is considered as the most effective therapy of Parkinson’s disease, which reduces all cardinal symptoms and which is improved since then. At the beginning pure levodopa was used with doses of 300 to 400 mg per day to achieve a good therapeutic success. This led to side severe and frequent effects, because the major part of the substance is converted in the gastro intestinal tract to dopamine and other catecholamines.
The first improvement was the application of additional L-Dopa decarboxylasis inhibitors, which reduced the peripheral conversion and can not pass the blood-brain-barrier to lower the side effects. Nowadays L-Dopa-therapy is always combined with decarboxylasion inhibitors and/or COMT-inhibitors.
The deterioration continues due to the proceeding process in the substantia nigra which can not be influenced. The long-term-side effects – motorial complications – are the known problem of L-Dopa-Therapy. These are the motorial late-complication, like dyskinesia, hyperkinesias or akinesia. Especially akinesia which appears with the highest possible dose after a long-term-treatment (End-of-dose akinesia) a combination between intake of L-Dopa and motion can be seen.
7.2 Other antiparkinson substances
All other pharmaceuticals which are used for the treatment of Parkinson’s disease can be classified into two classes - those substances which have an effect for the dopaminergal system and those with an effect for the basal ganglion cells.
The class of medication which effects the basal ganglion cells is the older one, modify the ganglion cells of the motoric system and show a lower effect. These are the class of anticholinergica and the NMDA-antagonists.
The huge class of dopaminerg substances are levodopa, monoaminoxidase-inhibitors (MAO-B-inhibitors), COMT-inhibitors and dopamine agonists.
7.3 Dopamine agonists
In practice dopamine agonists play an important role in the therapy of Parkinson’s disease, because the corresponding receptors are targeted directly. Most of the pharmaceuticals develop the effect directly at the D2-receptors, whereas the role of different types of receptors is still unknown. All dopamine agonists have a direct effect to the dopamine receptors; they differ in respect to half-life and special effects to different subtypes of dopamine receptors (D1, D2, D3). The latest dopamine agonists have advantages because of the long halflife, which improves the sense of a continuous postsynaptic activation of the receptors.
A mono therapy of Parkinson’s disease is possible with dopamine agonists and is used in early stages. In the course of time doses need to be increased with following side effects. Mono therapies are used especially with younger patients (before 40) due to early and severe L-Dopa-dyskinesia.
Clinical practice has shown that an add-on-therapy with dopamine agonists can reduce the dose of L-dopa or can reduce dyskinesia. Basically this is possible with all the dopamine agonists; the selection of the specific substance is due to the individual patient and the tolerance.
Older dopamine agonists are ergotic dopamine agonists (derived from ergotic-alkaloids), later substances are not ergotic anymore and do not have an ergotic-alkaloid structure.
Dopamine agonists with ergotic structure
Ergotic dopamine agonists are alpha-dihydroergocriptine (DHEC), bromocriptine, lisuride, cabergoline, pergolide.
Studies to the effectiveness of ergotic dopamine agonists are studies for the initial therapy, mono therapy and add-on-therapy. Theses studies are not comparable to each other. Basically these show a good effectiveness of dopamine agonists against dyskinesia and significant differences are proven. The effectiveness of dopamine agonists is weaker then this of ledodopa, although the use of initial therapy at the beginning of the disease can postpone the use of levodopa or can reduce its dose for a longer period.
For Bromocriptine there are ten-years-studies for mortality. Life tables were used for comparison. There are no differences between bromocriptine and levodopa in respect to mortality.
The side effects of this group of dopamine agonists are nausea and vomiting, further dizziness and hypersomnia. A publication from 2004 showed a suspicious increased incidence of valvulopathy under treatment with pergolide.
Dopamine agonists with non-ergotic structure
These later non-ergotic dopamine agonists are ropinirole, pramipexole, rotigotine and piribedile.
Studies for non-ergotic dopamine agonists show as well as ergotic substances a good effect against dyskinesia. These medications can be used at the beginning of a disease to postpone the use of levodopa or to reduce the dose of levodopa in case of an add-on-therapy.
Similar to ergotic dopamine agonists the first direct effects against the symptoms of Parkinson disease are weaker then with levodopa, but significant better then with placebo. The latest dopamine agonist rotigotine was developed for transdermal use as tape and is active over a period of 24 hours.
Non-ergotic dopamine agonist studies with imaging were done and under ropinirol the progressive loss of stratial F-Dopa measurement could be postponed. Another study with pramipexol could show that the beta-CIT-parameters could be reduced.
Pharmacoeconomic studies show that the cost-benefit ratio is about US $ 20,000. This incremental cost-effectiveness ratio as well the costs per QALY is under the US-average.
The side effects are less frequent than with ergotic dopamine agonists and also not so severe.
Apomorphine
The dopamine agonist apomorphine is one of the oldest used medications out of this group. It has a special position, because the treatment is done by bolus injections or infusion.
Two very qualitative good studies could be found. The first one reports a quick effect of this injection, but the effect does not last as long as L-dopa. The second one reports a significant improvement of the UPDRS-Score and the daily periods of “off-time” in comparison to placebo. This medication is used for emergency treatment.
The side effects are comparable with other dopamine agonists. There are nausea, vomiting, hypersomnia as well as psychiatric disorders (confusion, hallucination).
Comparisons of the effect of dopamine agonists
In a review the later dopamine agonists ropinirol, pramipexol and pergolide were compared to the older substance bromocriptin. The newer substances show a better effectiveness, the differences can not be interpreted due to a lack of direct comparability.
An unsystematic review compares the effectiveness of different dopamine agonists as add-on-therapy with levodopa. No difference could be found between the oral dopamine agonists.
Comparisons of dopamine agonists with other antiparkinsonian treatment
Some studies were done for comparison of COMT-inhibitors, MAO-B-inhibitors and dopamine agonists. A meta analysis included seven studies. The results show, that all dopamine agonists could reduce the L-dopa dose significantly.
One publication showed a comparable effectiveness of MAO-B-inhibitor tolcapone and dopamine agonist pergolide in respect to the UPDRS-Score and the PDQ. Only the scale quality of life of the PDQ the MAO-inhibitor tolcapone was superior to the dopamine agonist pergolide. The porgolide group had a higher incidence of side effects.
Costs of dopamine agonists
When the prices are compared dopamine agonists are the most expensive ones for Parkinson treatment. The authors of the relevant studies conclude, that due to the cost-benefit-ratios it is seen, that the higher cost for dopamine agonists can be compensated by other costs. The increased costs for medication can be compensated by reduced costs especially costs for inpatient care or postponed need for long term care.
Ethical considerations
From ethic view the reduced quality of life has to be considered. Therefore an effective and long lasting improvement of symptoms is primary focused. L-Dopa is still the gold standard although the late complications are known.
Side effects are a big issue in the studies. Many studies demonstrate high rates of dropout due to not tolerable side effects. There are no differences of the profile of side effects to levodopa. The dopamine agonists have comparable profiles, but some reported problems appear as more severe (e.g. vulvopathies under use of pergolid).
Dopamine agonists demonstrate that they do not deteriorate quality of life generally in comparison to other kinds of treatment.
8. Discussion
The strategy of treatment is depending of some factors. Recommendations of many experts show, that the treatment must be planned individually. Age at the beginning of therapy is very important. For younger patients (under 65 years) the risk for development of motoric fluctuations is much higher and therefore it is tried to use levodopa only at later stages of the disease.
The treatment of symptoms with levodopa and an additional decarboxyl-inhibitor is still the gold standard. Dopamine agonists have a fix place for the treatment of motoric fluctuations and dyskinesia, which are the late complications of a treatment with levodopa.
Dopamine agonists show a weaker effectiveness in comparison to levodopa. The positive effect of dopamine agonists are the late complications of levodopa. Early treatment with dopamine agonists can lower the increasing dose of levodopa or can postpone the use of levodopa.
Dpamine agonists could show significant improvement of symptoms of Parkinson disease in RCT. The advantage is especially for early stages of the disease an avoidance of the late complications of levodopa.
Motor fluctuations and end-of-dose dyskinesia can be reduced when dopamine agonists are used as add-on-therapy to levodopa. Significant improvements could be demonstrated according to the UPDRS-Score and the reduction of the daily “off-periods”.
9. Conclusions
The evidence of dopamine agonists for the treatment of Parkinson disease shows a good effectiveness as monotherapy for new incidences and for additional use for older patients with more severe stages of the disease.
Levodopa use can be postponed for months until years. The dose of levodopa can be reduced for years and the reduced late complications of levodopa can be demonstrated.
Motor fluctuations and dyskinesia can be reduced statistically significant. Dopamine agonists can moderate movement disorders due to the disease.
Dopamine agonists are not recommended to be a substitute for levodopa. The effectiveness is too weak and too cost intensive. The use can be considered as cost-effective in the described fields of indication.