New treatments for the motor symptoms of Parkinson’s disease

Abstract

Levodopa remains the most potent drug to treat motor symptoms in Parkinson’s disease (PD); however, motor fluctuations and levodopa-induced dyskinesia that occur with long-term use restrict some of its therapeutic value. Despite these limitations, the medical treatment of PD strives for continuous relief of symptoms using different strategies throughout the course of the illness: increasing the half-life of levodopa, using ‘levodopa-sparing agents’ and adding non-dopaminergic drugs. New options to ‘improve’ delivery of levodopa are under investigation, including long-acting levodopa, nasal inhalation and continuous subcutaneous or intrajejunal administration of levodopa. Long-acting dopamine agonists were recently developed and are undergoing further comparative studies to investigate potential superiority over the immediate-release formulations. Non-dopaminergic drugs acting on adenosine receptors, cholinergic, adrenergic, serotoninergic and glutamatergic pathways are newly developed and many are being evaluated in Phase II and Phase III trials. This article focuses on promising novel therapeutic approaches for the management of PD motor symptoms and motor complications. We will provide an update since 2011 on new formulations of current drugs, new drugs with promising results in Phase II and Phase III clinical trials, old drugs with new possibilities and some new potential strategies that are currently in Phase I and II of development (study start date may precede 2011 but are included as study is still ongoing or full data have not yet been published). Negative Phase II and Phase III clinical trials published since 2011 will also be briefly mentioned.

Keywords::

• adenosine
• adrenergic
• amantadine
• intrajejunal infusion of levodopa/carbidopa
• levodopa-induced dyskinesia
• long-acting dopamine agonists
• motor fluctuations
• Parkinson’s disease
• safinamide

Financial & competing interests disclosure

SH Fox has received financial support for clinical studies; consultancy and speaker fees from Astra Zeneca, Avanir, Eisai, Kyowa, Merz, Merck Serono, Novartis, Teva, Zambon. Funding sources for research from CIHR, Michael J Fox Foundation for Parkinson Research and Parkinson Society Canada, NIH. Salary support from UHN Department of Medicine Practice Plan. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Levodopa remains the most effective drug for all Parkinson’s disease symptoms.

• Improved availability via new nasal, subcutaneous and intrajejunal strategies may improve bioavailability and benefit in certain Parkinson’s disease subjects.

• Improved duration of action of levodopa can be achieved with COMT-I (Opicapone), ODM-101, and MAOB-I (rasagiline, safinamide).

• Adenosine A_2A antagonists may improve levodopa duration of action, but also induce levodopa-induced dyskinesia.

• Treatments for levodopa-induced dyskinesia continue to target overactive glutamatergic neurotransmission (e.g., long-acting amantadine, mGluR5 antagonists) but with variable efficacy.

• Other non-dopaminergic targets, to date, have not proven consistently efficacious in randomized controlled trials.

• Levodopa-resistant gait and balance symptoms remain difficult to treat; noradrenergic targets using L-threo-3,4-dihydroxyphenylserine and methylphenidate have had variable outcomes.