Treatment of motor fluctuations in Parkinson’s disease: recent developments and future directions

Abstract

Parkinson’s disease (PD) is characterized clinically by rest tremor, rigidity, bradykinesia and pathologically by degeneration of nigrostriatal dopamine neurons. Motor fluctuations (wearing off) and motor complications (dyskinesia) are common features of the long-term treatment of PD. Ongoing clinical and preclinical research has led to the discovery of promising new therapeutic targets that might prevent or reduce motor complications. Newer approaches modulating non-dopaminergic systems including adenosine A_2A antagonists, monoamine oxidase-B inhibitors, glutamatergic antagonists, adrenergic receptor antagonists and serotonergic agents are encouraging strategies for management of advanced PD. Recent developments in levodopa delivery formulations include duodenal infusion of a levodopa/carbidopa, new extended-release levodopa and oral pro-levodopa forms. Recent clinical trials revealed diverse but promising results raising the possibility of new therapeutic modalities for PD in the near future.

Keywords::

• deep brain stimulation
• dopaminergic treatment
• dyskinesias
• Parkinson’s disease
• wearing off

Financial & competing interests disclosure

A Ramirez-Zamora received speaker's bureau from Teva Neurosciences. E Molho received speaker's bureau and consultation fees from US World Meds, and received grant support from Merz, Cure Huntington's Disease Initiative, Teva Neurosciences, US World Meds, Auspex Pharmaceuticals and Acadia Pharmaceuticals. 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

• Chronic levodopa treatment in Parkinson’s disease (PD) is associated with the development of motor complications (fluctuations in motor response and dyskinesia) in the majority of patients, leading to marked disability.

• Several non-dopaminergic treatments are being evaluated as potential therapies to treat motor symptoms of PD.

• Adenosine A_2A receptors including istradefylline and preladenant have been shown to improve motor disability without inducing dyskinesia in animal models of PD and in small clinical trials.

• Glutamate antagonists have received increased attention in recent years as potential therapies for motor fluctuations and levodopa-induced dyskinesia. Several drugs have shown promising results in early preclinical trials, and further studies are needed.

• Adrenergic and serotoninergic agents are newer targets for treatment of motor fluctuations in PD, but the efficacy and applicability of these compounds remains unclear.

• Dopamine agonist extended-release formulations have shown reduction of ‘off’ time as adjunct therapies in subjects with advanced PD with motor fluctuations.

• Levodopa/carbidopa intestinal gel is a successful intervention to minimize motor fluctuations in advanced PD patients and enhance quality of life.

• A new extended-release levodopa formulation has been effective in reducing ‘off’ time with adequate tolerability in a large Phase III clinical trial.

• Deep brain stimulation remains an effective alternative for treatment of motor fluctuations in PD and newer technologies may provide improve outcomes providing better targeting, adjustable stimulation and correction for patient’s specific variance.