What causes on-off and wearing-off in Parkinson's patients?

Causes include progressive loss of nigrostriatal dopamine neurons, altered dopamine receptor sensitivity, and fluctuating levodopa plasma levels that produce unstable brain dopamine availability.

What motor symptoms occur during wearing-off and on-off?

Motor symptoms include dyskinesias (involuntary movements), dystonia (sustained painful contractions), freezing of gait, morning akinesia, and end-of-dose deterioration associated with levodopa fluctuations.

What neuropsychiatric symptoms appear during on and off periods?

Off periods may feature hallucinations, apathy, or anxiety; on periods can produce disinhibition, logorrhea, or hyperactivity. Neuropsychiatric signs can vary with levodopa responsiveness.

How does levodopa dosing and dietary protein affect wearing-off?

Levodopa dosing intervals determine wearing-off risk; protein competes with levodopa for absorption. Adjusting dose timing and reducing protein at dosing can improve absorption and reduce end-of-dose deterioration.

What are the predictable and unpredictable motor fluctuation profiles?

Predictable profiles include morning akinesia and wearing-off tied to dosing intervals; the unpredictable profile is sudden motor on-off fluctuations that occur independently of scheduled levodopa dosing.

On-off Phenomena and Wearing-off in Parkinson’s Disease

Q: What are the on-off and wearing-off phenomena in levodopa treatment?

On-off and wearing-off are motor fluctuation phenomena during levodopa therapy: on-off involves sudden alternation between improved motor function ("on") and immobility or freezing ("off"), while wearing-off is a predictable end-of-dose return of Parkinson's symptoms.

In this article we will talk about the on-off and wearing-off phenomena in levodopa treatment for Parkinson’s disease.

Introduction

Parkinson’s disease destroys the neuronal nuclei and circuits responsible for producing and distributing dopamine. The most important of these nuclei is the substantia nigra, since it is the first to undergo neurodegeneration as a consequence of various factors that have still not been fully explained. Among others, viral factors, toxic factors – MPTP –, mitochondrial factors, or genetic factors have been proposed.

In addition, involvement of noradrenergic neuronal circuits must be added; these are responsible for the “maintenance” functions of the rest of the body (cardiovascular system, respiratory system, wakefulness and sleep, etc.) and whose main neurotransmitter is norepinephrine. Furthermore, acetylcholine and the cholinergic system are also affected, producing effects such as tremor and postural rigidity.

Symptoms of Parkinson’s disease before the on-off and wearing-off phenomena occur

One of the symptoms of Parkinson is dystonia. These are defined as sustained muscle contractions that cause forced and painful postures for patients. These dystonias are associated with the fluctuation in dopamine levels as a consequence of the destruction of the substantia nigra. The duration of these dystonias can range between thirty minutes and five hours. Therefore, they are highly disabling, considerably reducing patients’ quality of life and increasing pain. Patients can reach “freezing” of movement in moderate and advanced stages of the disease.

To treat this symptom (and others), pharmacological medications such as levodopa are administered. The treatment is complex because levodopa is not dopamine itself, but a precursor, since dopamine cannot cross the blood-brain barrier of the nervous system formed by the meninges. Figuratively, one could say that it is a “wall” that protects us from external threats. Levodopa is the most effective treatment against the motor symptoms of Parkinson’s, although it is not free of side effects.

This medication does not have a permanent effect. It acts on some dopamine receptors located in the striatum, but ultimately these receptors are affected by neurodegeneration, or they become hypersensitive.

On-off and wearing-off phenomena after treatment

Once levodopa treatment has been assimilated, dyskinesias occur. They are defined as abnormal and exaggerated paradoxical movements such as tics or, again, muscle contractions (dystonias) and jerks. Dyskinesias occur as part of a phenomenon characterized by motor fluctuations when the efficacy of levodopa treatment begins to decrease throughout the day. Two types of phenomena occur: the on-off phenomenon and the wearing-off phenomenon.

The on-off phenomenon is a fluctuation of motor activity and is characterized by periods in which the patient alternates activity with a state of motor difficulty and even freezing of variable duration (from a few seconds to minutes). It appears that this phenomenon is associated with variations in the levodopa level in the blood.

In addition, during the “off” phenomenon, and as a consequence of pharmacological treatment, neuropsychiatric symptoms such as hallucinations, apathy, or anxiety may appear more frequently. But these are not exclusive to “off” periods. Also, during the “on” period disinhibition, logorrhea, or hyperactivity may appear. In fact, it has been proposed to subdivide the on-off symptoms (Martín Lunar et al., 2003).

On-off symptoms:

Motor on-off symptoms: We find two predictable profiles (morning akinesia and the wearing-off phenomenon) and one unpredictable profile (motor on-off phenomenon). Morning akinesia occurs when the interval between doses is longer than the effect of levodopa, producing a worsening of nocturnal motor symptoms that reach maximum intensity upon awakening. The wearing-off phenomenon is an end-of-dose deterioration that is closely related to levodopa dosing intervals; associated fluctuations occur whose latency progressively decreases as the disease advances.
Behavioral on-off symptoms: These would be the neuropsychiatric manifestations associated with the motor on-off phenomena.

Conclusion

Despite the above, levodopa is necessary and beneficial if there is responsiveness to the treatment. The above is intended to highlight the importance of properly controlling medication and the proteins ingested in Parkinson’s disease (since they are related in terms of blood absorption), and their consequences: during the on phenomenon responsiveness to antiparkinsonian treatment is greater and a clinical improvement occurs.