Managing advanced Parkinson’s disease Selecting the right treatment for your patient
Submitted by emily.kilby on Mon, 02/22/2021 - 15:23


Managing advanced Parkinson’s disease
Selecting the right treatment for your patient


Stuart H. Isaacson MD, FAAN


Parkinson Disease and Movement Disorders Center of Boca Raton, Florida, USA


Treatment strategies for OFF episodes in Parkinson’s disease (PD) continue to evolve.  Once OFF emerges, shared clinical decision-making can help guide initial adjustment to baseline levodopa regimen and / or the addition of adjunctive therapy.  Despite initial treatment, OFF episodes invariably continue to increase in frequency, severity, unpredictability, and daily impact [1].  This leads to ongoing consideration of “rational” polypharmacy throughout the course of PD.


Strategies to increase peripheral (plasma) levodopa include higher dose, more frequent timing, extended-release formulations, and inhibition of catechol-O-methyltransferase (COMT) [2,3].  Striatal dopaminergic tone can be increased with dopamine agonists and monoamine oxidase (MAO) inhibitors.  Non-dopaminergic adenosine and glutamate antagonists can also modulate striatal pathways.  Variability of intestinal levodopa absorption can be addressed with non-oral, on-demand formulations of levodopa and apomorphine.  Advanced surgical therapies include intestinal levodopa infusion; pallidal or thalamic ablation; and pallidal or subthalamic nucleus stimulation.  Additional therapies in development include novel targets, continuous subcutaneous infusions, and gene therapies [2,4].


The shared choice of which therapy to choose is determined by many factors.  The number and type of OFF episodes, OFF symptom severity, timing, and impact on daily life can help therapy selection.  Medication access, dosing, efficacy, tolerability, safety, clearance, and interactions are considered.  Patient comorbidities, concomitant medications, prior sensitivity to medication changes, and the presence (or absence) of dyskinesia, cognitive impairment, psychosis, and orthostatic hypotension can all impact treatment decisions.  Consideration of apomorphine subcutaneous infusion can help highlight the shared clinical decision-making process.



1.    Stocchi F. The levodopa wearing-off phenomenon in Parkinson’s disease: pharmacokinetic considerations. Expert Opin Pharmacother 2006;7:1399-407

2.    Olanow CW, Calabresi P, Obeso JA. Continuous dopaminergic stimulation as a treatment for Parkinson’s disease: current status and future opportunities. Mov Disord 2020;35(10):1731-44

3.    Poewe W, Mahlknecht P. Pharmacologic treatment of motor symptoms associated with Parkinson Disease. Neurol Clin 2020;38(2):255-67

4.    Pahwa R, Isaacson SH. Pharmacology and evidence-based strategies for current and emerging treatments for OFF periods in Parkinson’s disease.  J Clin Psychiatry 2020;82(1):SU19004BR2C.


February 2021