Management Of Levodopa-induced Dyskinesia Research Articles

Amantadine extended release capsules (GOCOVRI®) in Parkinson’s disease: a profile of its use in the USA

Amantadine extended release (ER) [GOCOVRI®], an NMDA receptor antagonist, is an important treatment option in the management of levodopa-induced dyskinesia (LID) and OFF episodes in patients with Parkinson’s disease (PD). Taken at bedtime, amantadine ER provides low plasma levels overnight and high plasma concentrations during the waking day (i.e. delayed release). In randomized, double-blind, placebo-controlled phase III trials in adults with PD, once-daily amantadine ER was effective in improving LID, reducing OFF time and increasing ON time without troublesome dyskinesia, compared with placebo. Control of motor complications with amantadine ER was evident throughout the day, with fewer transitions between motor states. The clinical benefits of amantadine ER in reducing the duration and impact of dyskinesia and OFF episodes were durable with long-term treatment. Amantadine ER is generally well tolerated, including in the long term, with the majority of adverse events being mild or moderate in severity.

The expression of cannabinoid type 1 receptor and 2-arachidonoyl glycerol synthesizing/degrading enzymes is altered in basal ganglia during the active phase of levodopa-induced dyskinesia

Management of levodopa-induced dyskinesias (LID) is one of the main challenges in the treatment of Parkinson's disease patients. Mechanisms involved in the appearance of these involuntary movements are not well known but modifications in the activity of different neurotransmitter pathways seem to play an important role. The objective of this study was to determine differences in the expression levels of the endocannabinoid system (ECS) elements that would support a role in LID. The basal ganglia nuclei, putamen, external segment of the globus pallidus (GPe), internal segment of the globus pallidus (GPi), subthalamic nucleus (STN) and substantia nigra (SN) were dissected out from cryostat sections obtained from two groups of parkinsonian monkeys treated with levodopa to induce dyskinesias. One group of dyskinetic animals was sacrificed under the effect of levodopa, during the active phase of LID, and the other group 24 h after the last levodopa dose (OFF levodopa). Biochemical analysis by real-time PCR for ECS elements was performed. CB1 receptor expression was upregulated in the putamen, GPe and STN during the active phase of dyskinesia and downregulated in the same nuclei and in the SN when dyskinetic animals were OFF levodopa. Changes in the 2-arachidonoyl glycerol (2-AG) synthesizing/degrading enzymes affecting the pallidal-subthalamic projections in dyskinetic animals OFF levodopa would suggest that 2-AG may play a role in LID. Anandamide (AEA) synthesizing/degrading enzymes were altered specifically in the GPe of untreated parkinsonian monkeys, suggesting that increased AEA levels may be a compensatory mechanism. These results indicate that the expression of the ECS elements is influenced by alterations in dopaminergic neurotransmission. On one hand, changes in CB1 receptor expression and in the 2-AG synthesizing/degrading enzymes suggest that they could be a therapeutic target for the active phase of LID. On the other hand, AEA metabolism could provide a non-dopaminergic target for symptomatic relief. However, further research is needed to unravel the mechanism of action of the ECS and how they could be modulated for a therapeutic purpose.

Clinical Aspects and Management of Levodopa-Induced Dyskinesia

In Parkinson's disease, one of the most troublesome dilemmas is the treatment of levodopa-induced dyskinesia. After a few years, chronic treatment with levodopa is associated with the development of dyskinesias. Strategies to delay or to reduce dyskinesias are based on the change of levodopa dosing or the early use of dopamine agonists. Dopamine agonists with different pharmacological profile are available. Our paper was aimed to analyse the clinical impact and the management of dyskinesias with dopamine agonists.

Management of levodopa-induced dyskinesias in Parkinson's disease

Long-term administration of levodopa in Parkinson's disease (PD) can cause motor complications such as dyskinesias and motor response fluctuations. An increased risk is associated with more severity and younger age at onset of PD, longer duration of treatment, and higher levodopa dose. Levodopa-induced dyskinesias (LID) consist of peak-dose dyskinesia, biphasic dyskinesia, and off-period dystonia. The pathophysiology of LID includes both pre- and post-synaptic mechanisms. Sensitized responsiveness of striatal dopamine D1, D2, and D3 receptors caused by dopamine depletion might be involved in the development of LID. The frequency and intensity of pulsatile stimulation on these receptors by dopaminergic drugs might also be a key etiologic factor, as could be altered glutamatergic regulation of medium spiny neurons in basal ganglia. Management of LID is based on continuous dopaminergic stimulation treatment such as low but frequent dosing of levodopa, administration of sustained-release levodopa formulation, and intraintestinal or subcutaneous infusion or transdermal delivery of dopaminergic drugs. Dopamine agonists given either as monotherapy or in combination with levodopa may be considered to prevent LID. Evidence suggests that amantadine, unilateral pallidotomy, and bilateral deep brain stimulation of the subthalamic nuclei are effective at avoiding the expression of LID.

Pallidal stimulation reduces treatment‐induced dyskinesias in “minimal‐change” multiple system atrophy

Deep brain stimulation therapy is increasingly gaining acceptance in the management of levodopa-induced dyskinesia and fluctuations in idiopathic Parkinson's disease. It is generally not recommended for the other forms of parkinsonism such as progressive supranuclear palsy or multiple system atrophy where the response to levodopa is usually poor and disease progression more rapid, making any benefit short-lived. Here, we present an autopsy-confirmed case of "minimal-change" multiple system atrophy in whom pallidal stimulation surgery was effective in abolishing severe levodopa-induced dyskinesia.

Drug treatment of Parkinson's disease in the 1990s. Achievements and future possibilities.

Advances in the medical treatment of Parkinson's disease have improved the disability related to complications of long term levodopa therapy, including motor fluctuations, dyskinesias and neuropsychiatric toxicity. A range of new dopamine agonists are in various stages of preclinical and clinical development. Cabergoline appears to be effective in improving moderate motor fluctuations, and a number of dopamine partial agonists that can act as either agonists or antagonists depending on the degree of denervation and receptor sensitivity are being investigated. Apomorphine represents a significant advance in the treatment of well developed motor fluctuations in selected patients who are able to master the technique of subcutaneous administration. The catecholamine-O-methyl transferase inhibitors are proving useful in phase III studies in the management of patients with moderate motor fluctuations. A role for glutamate antagonists is supported by animal and early clinical data, although the poor therapeutic index associated with the currently available nonselective, noncompetitive glutamate antagonists has prompted a search for more selective antagonists with less toxicity. The management of levodopa-induced dyskinesias remains a major therapeutic challenge. Some reports of dopamine partial agonists, selective D2 receptor antagonists and atypical antipsychotics being useful await confirmation. Neuropsychiatric toxicity probably remains the major dose-limiting adverse effect of levodopa and is a major reason for parkinsonian patients being admitted to nursing homes. The development of new atypical antipsychotics with improved therapeutic indices, along with the possible use of serotonergic antagonists, may improve management of this difficult problem. The challenge will be to fit these new forms of treatment into our present range of available drugs and to assess their relative role within the emerging framework of functional neurosurgery for parkinsonian disability.