Levodopa-Induced Dyskinesias in Parkinson’s Disease: Etiology, Impact on Quality of Life, and Treatments

Abstract

Levodopa is the most effective agent to alleviate motor dysfunction in Parkinson’s disease but its long-term use is associated with the development of dyskinesias. Although the pathogenic processes behind the development of levodopa-induced dyskinesias are still being elucidated, it appears that chronic administration of this short-lived agent results in nonphysiologic pulsatile stimulation of striatal neurons and abnormal firing patterns in the basal ganglia. Dyskinesias have been associated with decreased quality of life, and a number of methodologies to evaluate severity of dyskinesias are now available. Strategies to avoid, reduce, or eliminate dyskinesias include providing more continuous dopaminergic stimulation, administering an antidyskinetic agent, and surgery. Several new compounds that may provide an antidyskinetic effect are also under investigation.

Dyskinesia in Parkinson Disease - An Unmet Therapeutic Challenge

“…This leads to abnormal sensitization and responsiveness to glutamatergic cortical input 4 , and may reflect functional interactions between NMDA and dopamine receptors on medium spiny neurons in the striatum 7 . Changes in NMDA receptor signaling is consistent with the observed clinical benefit of NMDA receptor antagonists, such as amantadine, as adjuvant therapy in LID 1,3,5,8,9 . However, to date, assessment of the antidyskinetic efficacy of amantadine, and other NMDA receptor antagonists, has been limited to reports of small trials (e.g., 9 ).…”

“…Levodopa remains the most effective therapy for the treatment of motor symptoms in Parkinson Disease (PD) 1 . However, complications, such as motor fluctuations and dyskinesias, arise with chronic treatment.…”

Reduction of l-DOPA-Induced Dyskinesia by the Selective Metabotropic Glutamate Receptor 5 Antagonist 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]pyridine in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Lesioned Macaque Model of Parkinson's Disease

“…In this fashion, we sought to gain useful preclinical equivalents of proportion of time for which dyskinesia is present (Unified Parkinson's Disease Rating Scale part IV, item 32, or Movement Disorder Society-sponsored revision of Unified Parkinson's Disease Rating Scale item 4.1) (Fahn et al, 1987;Goetz et al, 2008), and diary measures of on-time, which incorporate the impact of troublesome dyskinesia, such as proportion of on-time jpet.aspetjournals.org without troublesome dyskinesia (Encarnacion and Hauser, 2008). These, unlike the conventional measures of the impact of dyskinesia used in the majority of nonhuman primate studies, have been successfully applied in phase III to provide a link through to successful clinical use .…”

Levodopa/Carbidopa Intestinal Gel for Treatment of Advanced Parkinson’s Disease: An Update on the Effects of Cognitive Functions

“…Long-lasting treatment with LD, however, is associated with the occurrence of motor fluctuations and dyskinesia. Such sideeffects, defined as LD-long-term-syndrome (LTS), negatively affect quality of life of patients and caregivers [3] [4]. The pathogenesis of these motor complications is rather complex [5], depending on endogenous factors (age, disease duration, duration of LD treatment, irregular absorption of oral LD formulations) as well as pharmacokinetic and pharmacodynamic properties of LD.…”

“…The pathogenesis of these motor complications is rather complex [5], depending on endogenous factors (age, disease duration, duration of LD treatment, irregular absorption of oral LD formulations) as well as pharmacokinetic and pharmacodynamic properties of LD. In particular, the relatively short plasma half-life of LD and the pulsatile dopaminergic stimulation play a significant role in the development of LTS [4] [5]. To overcome these limits, a variety of therapeutic strategies have been introduced with the aim of ensuring more continuous and stable stimulation of post-synaptic dopaminergic receptors, including prolonged-release dopaminergic agonists, mono-aminooxidase-B inhibitors (MAO-i), and catechol-O-methyl-transferase inhibitors (COMT-i) [6].…”