Introduction:
Dopamine is a neurotransmitter vital for transmitting signals between the brain and the body to support motor skills. People with Parkinson's have lower dopamine levels, making controlling and moving muscles challenging. Parkinson's disease occurs due to the damage of nerve cells or neurons in the substantia nigra of the brain. Substantia nigra is located in the midbrain dopaminergic nucleus, which is critical in dopamine production. Neurons in the substantia nigra are dopaminergic.
What Is Levodopa?
Levodopa is the precursor molecule to dopamine. Levodopa treats the symptoms of Parkinson's disease. Levodopa is commonly used as a dopamine replacement agent for the treatment. It is used to cure bradykinesia in Parkinson's disease (slow movements). Levodopa is a classical drug prescribed to a patient with Parkinson's disease if the symptoms worsen and are more difficult to control with other anti-Parkinson's drugs.
What Is the On-off Phenomenon in Parkinson's Disease?
In Parkinson's disease, there is damage to the substantia nigra, which is part of the brain. Levodopa is converted into dopamine in the central nervous system and periphery. Levodopa can cross the blood-brain barrier (BBB). Levodopa is often administered along with Carbidopa to minimize the side effects and increase the bioavailability of Levodopa. Dopamine decarboxylase inhibitors prevent the conversion of Levodopa to dopamine in the periphery, allowing more Levodopa to cross the blood-brain barrier. The Levodopa, after its activation, stimulates the post-synaptic dopaminergic receptors and produces the action on the target site in the periphery.
What Are On-Off Episodes in Levodopa Therapy?
Levodopa and Carbidopa are the gold standard treatments for Parkinson's disease for treating symptoms such as bradykinesia (slow movements), tremors, and rigidity. Unfortunately, the effectiveness of Levodopa is reduced. Levodopa acts by crossing the blood-brain barrier and gets converted into dopamine. Carbidopa helps in reducing the side effects of Levodopa. It prevents side effects such as nausea and vomiting. Carbidopa prevents the breakdown of Levodopa by monoamine oxidase enzyme. It prevents the conversion of Levodopa into dopamine in the peripheral tissues, thus preventing vomiting. Some Parkinson's disease patients have Levodopa at around three doses per day. If they start experiencing “off” episodes, the doctor will increase the dose to four or more times daily. Around half of the patients who take Levodopa experience wearing-off symptoms. Of these patients, one-half of the patients experience three to four hours per day.
What Does the On-off Phenomenon Feel Like?
The on-off phenomenon refers to a switch between mobility and immobility in Levodopa-treated patients, which occurs as an end of dose or worsening of the motor function and unpredictable motor fluctuations. Motor fluctuations are alterations between periods of improved mobility known as ‘on’ periods during which the patient responds to Levodopa and periods of impaired motor function or ‘off’ responses in which the patient responds poorly to Levodopa. But most people with Levodopa treatment experience off episodes when the symptoms return. The on/off episode happens when someone. Off-time is different for everyone and depends on how Parkinson's symptoms are ordinarily present. Tremor may be the first symptom to re-appear, and muscle stiffness or non-motor symptoms such as a change in mood, thinking, or fatigue. If there is a change in the symptoms, they interfere with daily activities. For many people, Levodopa does not work well, so Levodopa starts to wear off more, which triggers the on-off phenomenon. When the on-off phenomenon starts in Parkinson's disease, the person will feel better as a new dose starts to take effect and worsens before being due for another dose. The duration of ‘on’ becomes shorter, and the wearing-off happens sooner, which is soon for another dose of Levodopa. During the ‘on’ state, the person will become more energetic, and during the ‘off’ state, the person will become very stiff and slow. The person will have difficulty speaking and slurring their words. Motor fluctuations respond to controlled release forms of Levodopa.
What Is the Treatment for On-off Phenomenon in Parkinson's Disease?
The treatment method for the on-off phenomenon are as follows:
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People with Parkinson's disease can predict the on-off phenomenon. The effects of Levodopa will wear off after 3 hours.
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The on-off fluctuations are unpredictable and are more dangerous. So instead of switching to another type of Levodopa, the time between the Levodopa doses can be decreased by 30 to 60 minutes. In addition, dopamine agonists can be added that reduce the length of ‘off’ time.
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But it has side effects such as compulsive behaviors and visual hallucinations.
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COMT (Catechol-O-methyltransferase) inhibitors prolong the Levodopa effect but can increase the side effects.
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MAO (monoamine oxidase) inhibitors can be given along with Levodopa. Monoamine oxidase inhibitors block the action of the Monoamine oxidase enzyme. This enzyme breaks down dopamine. After taking Levodopa, the body converts it into dopamine.
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The dopamine levels will drop when the body uses each dose of Levodopa. This drop is called the ‘off’ episode.
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Parkinson's patients have gastrointestinal complications that interfere with the body’s absorption ability. When oral Levodopa is taken, it takes time for the body to absorb the medication, which may lead to delayed ‘on’ episodes.
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Some people develop ‘off’ episodes very soon. High doses of Levodopa increase the risk of ‘off’ episodes that cause more significant fluctuations in dopamine levels.
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This limits the fluctuations in dopamine and reduces the risk of ‘off’ episodes. So to avoid this, lower and more frequent doses of oral Levodopa with extended-release formula than a fast-acting option are used.
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Enteral Levodopa is recommended. In this type, the Levodopa is infused continuously through a tube into the intestinal tract to provide a steady dose stream. Inserting a tube requires surgery. During ‘off’ episodes taking fast-acting medications like sublingual Apomorphine can give quick relief. In some cases, doctors do deep brain stimulation in which implant electrodes are placed in the brain, and a small internal pulse generator is placed in the abdomen or chest.
Conclusion:
When the medication Levodopa does not work well, most patients experience the ‘off’ symptoms, and the symptoms return or worsen. The signs harm the quality of life. The on-off phenomenon is an unfortunate problem in parkinsonism, while several ways exist to combat the condition. The on-off phenomenon is a motor disorder that affects the quality of life of patients. Although many strategies are developed to manage this phenomenon, more research is needed to understand and develop more effective treatments.
