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The “Freezing of Gait” Effect From Levodopa Management of Parkinson Disease

Updated: May 22

Why does this medication side effect occur, and how can 3D printing help?


Do you ever wonder exactly how our bodies move? Do you marvel at the complex processes that all have to work together to produce smooth and coordinated movement of the arms and legs?


Most of the time, we take our ability to move for granted. Often, it isn’t until this ability is taken away or seriously impacted by an injury or a medical condition that we begin to appreciate our capacity for movement.


What is Parkinson Disease?

Parkinson disease (PD) is a movement disorder characterized by insufficient production of dopamine by specialized nerve cells called basal ganglia in the brain.


Dopamine is a type of neurotransmitter, a chemical substance released by nerve fibers, that is responsible for sending messages to other nerves throughout the body.


Dopamine plays major roles in movement, memory, behavior, and mood.


In PD, low dopamine levels cause several movement-related symptoms, such as:

  • involuntary movements at rest called resting tremors;

  • the slowness of movement;

  • difficulty initiating movement;

  • stiffness of the torso, arms, and legs;

  • balance and coordination impairments.

As the disease progresses, simple everyday tasks like walking, talking, eating, and swallowing become more complex. And the risk of falling increases.


How is Parkinson Disease Treated?


First-line PD treatments involve oral pharmaceuticals such as Levodopa. Levodopa increases dopamine levels to provide symptom relief.


Levodopa is an amino acid precursor to dopamine. Levodopa can cross the blood-brain barrier (BBB), whereas dopamine cannot. The BBB is formed by a group of highly selective cells that prevent microorganisms and specific substances circulating in the blood from entering the brain. Levodopa is used instead of dopamine to treat PD because dopamine replacements would be unable to cross the BBB to target nerve cells in the brain.


After Levodopa crosses the BBB, it converts to dopamine throughout the central and peripheral nervous systems. This effectively reduces PD symptoms, especially bradykinesia (slowness of movement).


What is Freezing of Gait?


Freezing of gait is the episodic inability to initiate or produce forward-stepping movement physically. Freezing of gait is a common symptom of advanced PD that often appears prior to initiating Levodopa treatment. Initially, the administration of Levodopa helps minimize and manage these freezing episodes during early PD stages.

These freezing episodes can happen before the administration of the next expected Levodopa dose as the beneficial effects of the medication wear off over time. As PD progresses, these upsetting periods of immobility also may occur after long-term use of Levodopa.


Both pharmacokinetic and pharmacodynamic factors contribute to the freezing of gait. In other words, problems with the delivery of adequate dosage of the drug and the unique ways each patient metabolizes the drug result in these motor fluctuations.


Wearing Off Effect


The “wearing off” effect describes the decrease of Levodopa’s beneficial impacts on PD symptoms after long-term Levodopa use (~20+ years). Wearing off occurs in most patients with PD (~77%), resulting in the progression of PD motor symptoms such as freezing of gait.

Progressive re-emergence of motor symptoms prior to the next scheduled Levodopa dose indicates that Levodopa loses its potency over time without increasing the frequency of administration or the dosage. Higher dosages may have toxic effects. Evidence suggests that consistent delivery of Levodopa may thwart motor fluctuations.


This “wearing off” effect may be due to the degeneration of dopaminergic neurons, which cannot up-take available Levodopa for conversion to dopamine, resulting in freezing of gait.4,6 Levodopa resistance may also arise from non-dopaminergic lesions and pathologies as PD progresses.


Levodopa Half-Life


Half-life is the time it takes for the active substance in an administered drug to be reduced by half in the body. Levodopa has a relatively short half-life of around 60 minutes. This can be extended to around 90 minutes when Levodopa is combined with other medications such as carbidopa.


This feature of Levodopa drug metabolism necessitates frequent, repeated administrations throughout the day to maintain an effective therapeutic dose within the body.


Since the half-life of Levodopa is so short, freezing of gait more frequently occurs in the mornings prior to a patient’s first dose. After a night’s sleep lasting between 6 to 8 hours, the medication is no longer at an effective therapeutic dose in the body.


The 3D Printing Solution


3D printing of pharmaceuticals enables the production of precision medications that are customized to the individual. Personalization of medications facilitates frequently changing dosages as the “wearing off” effect occurs.

Customized formulations of 3D-printed tablets may also consider how rapidly a person metabolizes the medicine. These individuals may require an extended-release drug to remain in the therapeutic window. This reduces the treatment burden caused by frequently needing to take Levodopa every few hours.


One solution to reduce morning episodes of freezing of gait is a 3D-printed delayed-release Levodopa tablet. This version of Levodopa does not release until 8 or 9 hours after administration. This allows a patient with PD to take the 3D-printed pill before bedtime. The medication releases closer to when the patient wakes up to prevent immediate freezing of gait in the morning.


Conclusion


As technology advances, customizable medications become more of a reality. Improving pharmaceuticals considers the varying aspects of pharmacokinetics, pharmacodynamics, and currently known drug side effects.


The 3D printing platform enables frequent dosage changes and more accurately times the release of Levodopa. These alterations in the way the drug is manufactured improve overall drug delivery and have the potential to effectively reduce episodes of freezing of gait in patients with PD.

 

Laxxon Medical is dedicated to engineering patented 3D pharmaceutical solutions which optimize products and benefit patients. Our goal is to establish SPID®-Technology as a manufacturing process that has the individual and the pharmaceutical partner in mind.




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