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On-off phenomena? Wearing-off? Why are they important in Parkinson’s disease?


Parkinson’s disease destroys the neuronal nuclei and circuits that are responsible for distributing and generating dopamine. The most important of these nuclei -but not the only one- is the substantia nigra: it is the first to suffer neurodegeneration as a consequence of several factors that have not yet been explained. Among others, viral, toxic (MPTP), mitochondrial or genetic factors have been proposed. To this must be added the involvement of noradrenergic neuronal circuits, which are responsible for the “maintenance” functions of the rest of the body (cardiovascular system, respiratory system, wakefulness and sleep, etc.) and whose main transmitter is norepinephrine. In addition, acetylcholine and the cholinergic system are also affected, producing effects such as tremors and postural rigidity.

Symptoms of the disease

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

Pharmacological drugs such as levodopa are administered to treat this symptom (and others). 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 – in a graphic way, it could be said that it is a “wall” that protects us from external threats. Levodopa is the most effective treatment for the motor symptoms of Parkinson’s, although it is not without side effects.

Levodopa does not have a permanent effect. It acts on some dopamine receptors found in the striatum, but eventually these receptors are affected by neurodegeneration, or become hypersensitive.

What happens when levodopa treatment has been assimilated?

Dyskinesias: abnormal and exaggerated paradoxical movements such as tics or, again, muscle twitching (dystonia) and jerking. Dyskinesias occur as part of a phenomenon characterized by motor fluctuations when the efficacy of levodopa treatment begins to diminish 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 seems that this phenomenon is associated with variations in the blood levodopa level.

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 the “off” periods: during the “on” period, disinhibition, verbosity, or hyperactivity may appear. In fact, it has been proposed to subdivide the on-off symptoms (Martín Lunar et al., 2003).

On-off symptoms:

In spite of the above, levodopa is necessary and beneficial if there is receptivity to treatment. All of the above is intended to highlight the importance of correctly controlling the medication and proteins ingested in Parkinson’s disease (since they are related in terms of absorption into the blood), and its consequences: during the on-phenomenon, receptivity to antiparkinsonian treatment is greater and there is a clinical improvement.

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