The trajectory of the use of dopamine replacement therapy (DRT) in Parkinson's disease (PD) is variable and doses may need to be increased, but also tapered. The plan for dose adjustment is usually done as per drug information recommendations from the licensing bodies, but there are no clear guidelines with regards to the best practice regarding the tapering off schedule given sudden dose reductions of drugs such as dopamine agonists may have serious adverse consequences. A systematic literature search was, therefore, performed to derive recommendations and the data show that there are no controlled studies or evidence-based recommendations how to taper or discontinue PD medication in a systematic manner. Most of the data were available on the dopamine agonist withdrawal syndrome (DAWS) and we found only two instructions on how to reduce pramipexole and rotigotine published by the EMA. We suggest that based on the available data, levodopa, dopamine agonists (DA), and amantadine should not be discontinued abruptly. Abrupt or sudden reduction of DA or amantadine in particular can lead to severe life-threatening withdrawal symptoms. Tapering off levodopa, COMT inhibitors, and MAO-B inhibitors may worsen motor and non-motor symptoms. Based on our clinical experience, we have proposed how to reduce PD medication and this work will form the basis of a future Delphi panel to define the recommendations in a consensus.

/pdf/implications-of-dopaminergic-medication-withdrawal-in-3aawend3ig.pdf

Implications of dopaminergic medication withdrawal in Parkinson’s disease

Parkinson’s disease (PD) is a very common extrapyramidal movement disorder and currently the world’s fastest growing neurological disorder. In the course of disease progression, a majority of PD patients develop severe motor fluctuations which often cannot be adequately treated with common oral anti-Parkinsonian medications. With continuous subcutaneous apomorphine infusion (CSAI), levodopa–carbidopa intestinal gel infusion (LCIG), and deep brain stimulation (DBS), there exist three effective treatment options for advanced PD patients with motor fluctuations. In this study, we analyze the dynamics of implementation for these treatments in Germany over the years 2010–2017 based on the diagnosis-related group statistics and structured quality reports. All three intensified therapy measures are increasingly applied in Germany. The mean age of therapy implementation is rising and more male than female patients receive treatments. Although DBS is provided primarily in university hospitals with a caseload of at least two procedures per month, there exists a substantial proportion of DBS procedures which is conducted in hospitals with only a low caseload. Most of the drug pump implementations (CSAI and LCIG) are conducted in a large number of hospitals with an overall low case number. As we detect a strong rise of the implementation of these device-based therapies, it will be a challenging task to satisfy patient need and perpetuate high standards for these specialized procedures in the future.

Dynamics of device-based treatments for Parkinson’s disease in Germany from 2010 to 2017: application of continuous subcutaneous apomorphine, levodopa–carbidopa intestinal gel, and deep brain stimulation

Since the 1960s many substance classes have been introduced for treatment of idiopathic Parkinson's disease. The most important and effective medication is levodopa (L-dopa) always in combination with a decarboxylase inhibitor. In addition, dopamine agonists, monoamine oxidase B (MAO-B) inhibitors, catechol-o-methyltransferase (COMT) inhibitors, N‑methyl-D-aspartate (NMDA) antagonists and very rarely anticholinergics are administered depending on the motor symptoms, age and a multitude of other factors. Fortunately, within the substance classes there are various preparations, which also have different effects. In order that the advantages of the individual medications can be exploited and undesired effects and interactions can be avoided, one must come to terms with the complex data and the pharmacology of the medication. In addition important aspects are interactions and reciprocal actions. In the foreseeable future, different substance classes are to be expected.

[Pharmacological treatment of motor symptoms in Parkinson's diseases].

Die Entwicklung motorischer Fluktuationen und Dyskinesien charakterisiert den Ubergang vom fruhen zum fortgeschrittenen Parkinson-Stadium. Aktuelle Strategien der oralen Therapie umfassen die starkere Verteilung von Levodopa, ihre verlangerte Wirkdauer durch Gabe von Enzymblockern (MAO- und COMT-Hemmern) und Dopaminagonisten. Mit fortschreitender Krankheit wird die Motorik jedoch zunehmend abhangig von der Levodopa-Resorption und dessen Bioverfugbarkeit im Plasma, was schlieslich zu motorischen Fluktuationen fuhrt. Wenn Patienten nach der optimierten oralen Medikationsanpassung weiterhin funktionelle Einschrankungen bei den Aktivitaten des taglichen Lebens haben, sollten Infusionstherapien mit Apomorphin oder Levodopa und operative Verfahren (Tiefe Hirnstimulation) in Betracht gezogen werden. Im Vergleich zur pulsatilen oralen Therapie kann durch die Infusion von Apomorphin oder Levodopa eine kontinuierlichere striatale Stimulation der Dopaminrezeptoren erzielt werden, was zu einer signifikanten Reduktion der off-Zeiten und Dyskinesien, insbesondere der peak-dose-Dyskinesien, fuhrt. Langjahrige Erfahrungen mit diesen Behandlungen zeigen bedauerlicherweise, dass die motorischen Komplikationen durch eine kontinuierliche Stimulation des Rezeptors nicht komplett reversibel sind, was darauf hindeutet, dass Veranderungen der synaptischen Plastizitat und Konnektivitat nicht einfach ruckgangig gemacht werden konnen, nachdem sie erst einmal etabliert sind. Wunschenswert ware ein Einsatz zu einem fruheren Zeitpunkt, zu dem sich motorische Komplikationen erst entwickeln und nicht in einem spaten Stadium, wenn diese schon ausgepragt sind. Vorlaufige Ergebnisse beim fruhen Einsatz der Tiefen Hirnstimulation oder einer fruhen Pumpenbehandlung legen nahe, dass dies erfolgsversprechend erscheint, aber bevor es in der klinischen Praxis implementiert wird, bedarf es auch einer detaillierten Kosten-Nutzen-Analyse.

Intrajejunale Levodopa- und Apomorphin-Infusion zur Therapie motorischer Komplikationen bei fortgeschrittener Parkinson-Krankheit

Parkinsonian Drugs: Indications

Das idiopathische Parkinson-Syndrom ist nach der Alzheimer Erkrankung die zweithaufigste neurodegenerative Erkrankung und im
 fortgeschrittenen Stadium durch zahlreiche Besonderheiten gekennzeichnet. Neben nicht-motorischen Symptomen stehen oft motorische
 Komplikationen im Vordergrund, die mit pulsatilen oralen Therapien nur unzureichend verbessert werden konnen. Mithilfe der kontinuierlichen
 dopaminergen Stimulation lassen sich jedoch auch im fortgeschrittenen Stadium Optimierungen vornehmen, die neben der Verbesserung
 motorischer und nicht-motorischer Symptome auch eine hohere Lebensqualitat erzielen konnen. Etabliert hat sich in diesem Zusammenhang die
 kontinuierliche subkutane Gabe von Apomorphin mittels Medikamentenpumpe, deren Nutzen, Indikationen, Anwendungsbeschrankungen und praktische
 Umsetzung in dieser Expertenempfehlung ausfuhrlich dargestellt werden. Besonders hervorzuheben ist das vorteilhafte therapeutische Fenster
 der Apomorphin-Pumpentherapie, das durch einfache medikamentose Titration bei einem schnell reversiblen Verfahren optimal ausgenutzt werden
 kann. Im vorliegenden Artikel werden die Ergebnisse eines Experten-Meetings zur Apomorphin-Therapie vorgestellt, das am 6. Juli 2016 in
 Frankfurt am Main stattgefunden hat.

Practical use of continuous apomorphine infusion via pump

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Practical use of continuous apomorphine infusion via pump