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Motor Fluctuations in Parkinson’s Drug Efficacy Over Time

Each levodopa dose’s duration of efficacy tends to decrease as Parkinson’s disease progresses. These fluctuations result in alternating phases of symptom control (ON periods) and lack of control (OFF periods) throughout the day. 

You may notice that the duration of levodopa efficacy on your symptoms is decreasing as your disease progresses. You then cycle through phases of adequate control of your symptoms and phases during which symptoms are harder to manage. 

These cycles are referred to as motor fluctuations of levodopa efficacy over time.

In the first years of treatment, levodopa response is typically stable and predictable. You get a sufficient response by taking your dose, meaning your symptoms disappear completely over a long period of time. This long efficacy duration is due to your neurons’ ability to store the dopamine you give them and release it gradually. 

This storage capacity is comparable to your car’s gas tank. Your doses of levodopa gradually fill your tank. Taking them every day brings the tank back to full so you never run out of gas.

The amount of dopaminergic neurons and the storage capacity decrease as the disease progresses. The usable supply of dopamine is equivalent to a few hours.

It is as if your car’s gas tank became smaller and smaller and you were constantly on reserve, with levodopa freely circulating in your body. Your autonomy until the next filling becomes shorter and shorter and you can quickly find yourself on empty.

ON and OFF periods refer to different drug efficacy levels you go through. They can also be referred to as ‘’ON-state’’ and ‘’OFF-state.” 

When your symptoms are controlled and you feel functional, you are in an ON period. Your medication’s efficacy is at its highest potential and you obtain all the benefits from it during this period. Your gas tank is full and you can drive without a worry.

During OFF periods, Parkinson’s disease symptoms resurface and affect your functioning. Your medication is therefore not as effective. You have no more gas, so you have come to a stop or are about to. Your car is parked on the curb and you become a spectator.

OFF periods usually occur:

  • In the morning, upon waking up: Your body has absorbed all the levodopa you gave it the night before. 
  • Close to your next dose: Your body has absorbed all the levodopa you gave it during your previous dose. This period is known as and end-of-dose depletion of therapeutic effect.

The occurrence of these OFF episodes periods is predictable during the intermediate stages of the disease. In later stages, the onset of these episodes periods may become more sudden and unpredictable.

Fluctuations are associated with instability in levodopa’s therapeutic response. These fluctuations often go unnoticed, especially in the early stages of their appearance. 

If you experience an increase in energy and a noticeable improvement in your symptoms within an hour of your first morning dose, you will likely go through several ON-OFF cycles during the day. Your symptoms will then alternate throughout the day, depending on how much levodopa you are taking.

Here are some questions you can ask yourself to determine if you are experiencing motor fluctuations:

  • Are my symptoms better controlled during certain moments in the day?
  • Do I feel a lot better one or two hours after my levodopa dose?
  • Do the times when my symptoms are poorly controlled occur before a new dose?
  • Do my typical Parkinson’s symptoms come and go with my medication?

A dose’s effect is not instantaneous and may take up to one to two hours. This can be confused with OFF periods of fluctuations.

To better take control of these fluctuations and adapt your levodopa doses with your neurologist, you need to understand: 

  • How long it takes for a levodopa dose to take effect. Generally, levodopa produces its maximum effect

    within 60 to 90 minutes of taking it when taken on an empty stomach.

    1. If you feel good and functional after this time, you are probably receiving a suitable levodopa dose.
    2. On the other hand, your dose may be insufficient if your symptoms remain unaffected.

Do not confuse levodopa’s repeated ineffectiveness with occasional non-functional doses, especially during the afternoon. This will be addressed below.

  • How long a dose’s efficacy lasts. During the day, observe all your intakes and notice how long their effect lasts.

Once you have this information, your neurologist can better adjust the interval of your doses. As a general rule, this interval should be slightly less than the duration of each dose’s effect. This way, the next dose has time to take effect while the previous dose loses its effect.

You are the person who can best recognize these changes. During OFF periods, your body is sending you a message about its lack of dopamine. 

Your loved one is also a daily witness to these fluctuations.

However, you tend to be in ON episodes when you visit your neurologist. You therefore need to inform them of these fluctuations and the information you have gathered regarding the time of onset and duration of your dose’s effect.

Motor fluctuations are not inevitability of Parkinson’s disease. They can be treated. You and your neurologist can agree on a new treatment plan that likely involves reducing the intervals between doses or adding new medications.

You can improve the efficacy of your levodopa by following certain rules:

  • Do not take high-protein foods within 60 minutes before or after your medication. They limit the absorption of your medicine and delay its effect
  • Take your levodopa with at least half a glass of water. This liquid will send your pill directly to where it is effective and thus reduce the effect’s delay
  • Keep levodopa tablets with you so that you can take them as needed, for example, during a special outing or activity
  • Stress and anxiety tend to “burn” levodopa more quickly, thereby reducing the effect’s duration
  • Physical activity also absorbs more levodopa. Advance your intake time to avoid falling into an OFF episode. You will take your next dose at your established interval 

In most cases, levodopa doses are ineffective for two main reasons:

  • You took your medication too close to a snack or meal
  • Your levodopa dose is insufficient to bring you to an ON period 

In the latter case, see if your neurologist recommends taking an additional half to one dose of levodopa. You will then have to readjust your dosing interval.

Do not try to adjust your levodopa dosage yourself. You may experience one of levodopa’s serious side effects, dyskinesia . Speak with your neurologist or nurse. They may also suggest alternatives to levodopa tablets, such as a levodopa pump or emergency apomorphine injections.

Once you and your neurologist have found the right dose of each medication for you, it is unlikely that it will change significantly over time. 

However, as the disease progresses, the need for dopamine and the total daily dose required increase. It is obtained by reducing the intervals between dose intake

Other therapeutic options, such as apomorphine injections, levodopa pumps and surgery are also available if these motor fluctuations can no longer be managed.

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