Continuous dopaminergic stimulation in advanced PD
Submitted by emily.kilby on Mon, 03/01/2021 - 17:14

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Continuous dopaminergic stimulation in advanced PD

 

Rajesh Pahwa, Laverne Joyce Rider Professor of Neurology, University of Kansas Medical Center, Kansas City, Kansas, USA

 


After 50 years, levodopa remains the mainstay treatment for Parkinson’s disease (PD).  However, as the PD progresses, patients on chronic levodopa therapy tend to develop motor and non-motor fluctuations, characterised by end-of-dose wearing off and unpredictable on-off episodes, as well as dyskinesias, making management increasingly challenging [1].  Within six years of diagnosis, around 40% of all patients on levodopa will experience motor fluctuations [1].

In early PD, when neuronal firing becomes phasic, continuous receptor stimulation is maintained by a buffered level of dopamine.  However, as the disease progresses and dopamine terminals degenerate, the dopamine buffering capacity in striatal neurons is reduced.  When that happens, the response to each dose of levodopa is shortened and the therapeutic window is narrowed, and patients develop peak-dose dyskinesias and more frequent and unpredictable offs [2].  Intermittent levodopa may also induce abnormal striatal glutamate transmission, activating NMDA receptors and promoting dyskinesia [3].  

Off fluctuations may also relate to the short half-life of levodopa and the fact that oral levodopa is dependent on the passage through the stomach before absorption in the proximal intestine; this passage can be complicated by the delayed gastric emptying frequently associated with PD [4].

Continuous dopaminergic stimulation (CDS) is a treatment strategy for PD that aims to avoid or reduce the fluctuations and dyskinesias associated with the chronic use of levodopa; it is an attempt to replicate the physiologically ‘normal’ tonic stimulation of post-synaptic dopamine receptors [5].  Approaches to delivery of CDS include slowing, and thereby extending, the release of oral levodopa, delaying its metabolism using a decarboxylase inhibitor and catechol-O-methyl transferase inhibitor, and bypassing the gastric mucosa with the use of device-aided continuous infusion of medication.


References
1.    Ahlskog JE, Muenter M. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature.  Mov Disord 2001;16(3):448-58


2.    Jankovic J. Motor fluctuations and dyskinesias in Parkinson’s disease: clinical manifestations. Mov Disord 2005;20(suppl 11):S11-6


3.    Gardoni F, Bellone C.  Modulation of the glutamatergic transmission by dopamine: a focus on Parkinson, Huntington and addiction diseases. Front Cell Neurosci 2015;9(25): doi: 10.3389/fncel.2015.00025


4.    Pfeiffer RF, Isaacson SH, Pahwa R. Clinical implications of gastric complications on levodopa treatment in Parkinson's disease.  Parkinsonism Relat Disord 2020;76:63-71


5.    Nutt JG. Continuous dopaminergic stimulation: is it the answer to the motor complications of levodopa? Mov Disord 2007;22:1-9

 

 

UK-APO-2100027
February 2021