Management challenges with advancing disease
Submitted by emily.kilby on Thu, 02/18/2021 - 14:19

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Management challenges with advancing disease

 

Stuart H. Isaacson MD, FAAN

 

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


In patients with Parkinson’s disease (PD), the initial effect of levodopa on motor symptoms is typically robust and durable beyond each dose. However, this so-called “long duration response” invariably wanes, often beginning in the first year after initiation of levodopa therapy [1]. Then, with loss of benefit from a levodopa dose, motor symptoms return (‘OFF episodes’) [2]. 

 

OFF episodes can be characterized by both pathophysiology and / or timing in relation to levodopa dose. Both central (presynaptic, striatal denervation, postsynaptic, pharmacodynamic) [3] and peripheral (delayed intestinal, competitive protein, gut bacteria) [4] mechanisms have been described, which coupled with the short plasma half-life of levodopa, can lead to OFF episodes.  OFF episodes are increasingly frequent throughout the multi-decade course of PD, despite increasing pharmacotherapy.  OFF episodes may occur unexpectedly, or be predictable in relation to time of day (i.e. morning), meals (i.e. postprandial), and other external factors (e.g. exercise).  

 

OFF episodes may be motor, heralded by nonmotor symptoms, or can be predominantly nonmotor.   OFF symptoms will continue to increase in severity until the benefit of the next levodopa dose begins, which may be delayed in onset, suboptimal in benefit, or fail to provide symptom benefit.  OFF episodes impact daily activities, employment, quality of life, and (when balance is affected) falls [5].

 

Delayed ON of the first daily dose of levodopa, known as morning akinesia or early morning OFF (EMO), can significantly impact quality of life and impair daily activities [5].  In a large European, observational study it was found that EMOs occur in nearly 60% of PD subjects across all stages of disease.  Furthermore, at least 50% of patients observed who were taking prolonged-release dopamine agonists were reporting EMOs [6].  Morning akinesia can occur due to a delay in gastric emptying, impaired intestinal absorption, pharmacodynamic effects, or other mechanisms [7-10]. Alternative delivery of dopaminergic therapy by a non-oral route may therefore be useful in patients with PD and gastroparesis.  

 

Subcutaneous apomorphine injection is used by patients with PD in the OFF state to provide a rapid and reliable ON.   The AM-IMPAKT trial, a multicenter, open-label investigation, confirmed the efficacy and clinical utility of subcutaneous apomorphine for the reversal of EMO [11].  Patients achieved an ON state an average of 37 minutes faster with apomorphine than with oral levodopa, representing a 61% improvement in time to ON.  Apomorphine patients also had significant improvement on quality of life and global impression scales.

 

As our understanding develops of the mechanisms and course of the challenges presented by advancing PD – a consequence of both the disease itself and levodopa treatment, we can become better equipped to manage our patients and provide them with a more predictable daily life.

 


References

1.    Zappia M, Bosco D, Plastino M et al. Pharmacodynamics of the long-duration response to levodopa in PD. Neurology 1999;53(3):557-60


2.    Stocchi F, Jenner P, Obeso JA. When do levodopa motor fluctuations first appear in Parkinson's disease? Eur Neurol 2010;63(5):257-66


3.    Calabresi P, Picconi B, Tozzi A et al. Direct and indirect pathways of basal ganglia: a critical appraisal. Nature Neuroscience 2014;17(8):1022-30


4.    Stocchi F. The hypothesis of the genesis of motor complications and continuous dopaminergic stimulation in the treatment of Parkinson’s disease.  Parkinsonism Relat Disord 2009;15(Suppl 1):S9-15


5.    Chapuis S, Ouchchane L, Metz O et al. Impact of the motor complications of Parkinson's disease on the quality of life. Mov Disord 2005;20(2):224-30


6.    Rizos A, Martinez-Martin P, Odin P et al. Characterizing motor and non-motor aspects of early-morning off periods in Parkinson's disease: an international multicenter study. Parkinsonism Relat Disord 2014;20(11):1231-5


7.    Chaná P, Kuntsmann C, Reyes-Parada M, Sáez-Briones P. Delayed early morning turn "ON" in response to a single dose of levodopa in advanced Parkinson's disease: pharmacokinetics should be considered. J Neurol Neurosurg Psychiatry 2004;75(12)1782-3


8.    Stocchi F. The levodopa wearing-off phenomenon in Parkinson’s disease: pharmacokinetic considerations. Expert Opin Pharmacother 2006;7:1399-1407


9.    Nyholm D, Lennernas H. Irregular gastrointestinal drug absorption in Parkinson’s disease. Expert Opin Drug Metab Toxicol 2008;4:193-203


10.    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


11.    Isaacson S, Lew M, Ondo W et al. Apomorphine subcutaneous injection for the management of morning akinesia in Parkinson’s disease. Mov Disord Clin Pract 2017;4(1):78-83.

 

 

UK-APO-2100026
February 2021