Movement Problems That Develop Later: Dyskinesias, Motor Fluctuations, and Treatment with Levodopa Adjustments

Mr. Owens: "Every time I go to the gym, my medicine quits working."
 Mr. Owens likely has a "short-duration" levodopa response that is affected by exercise. Exercise typically "burns the fuel faster," that is, the levodopa effect dissipates more quickly. Mr. Paul should plan ahead. If he finds that he usually lapses into an off-state three-fourths of the way through his exercise routine, he should plan on a dose of carbidopa/levodopa about 45-60 minutes before that happens. All subsequent doses will need to be moved up accordingly so that he does not have a large gap in his schedule.

 The short-duration levodopa response. The upper graph depicts the buildup and decline of levodopa (and dopamine) in the brain after a dose of carbidopa/levodopa. Parallel to this is improvement in parkinsonism, shown in the lower graph. In this hypothetical case, the initial parkinsonian symptoms are severe until the levodopa effect kicks in, followed by the on-state. Later the effect wears off, linked in time with the decline of brain levodopa and dopamine concentrations.

 Mrs. Paul: "I got mixed up and took a double dose of my carbidopa/levodopa. Now I have these uncontrollable movements throughout my body. Do you have the antidote?"
 Mrs. Paul is describing dyskinesias from a relative overdose of levodopa. Is that worrisome? No. This will resolve on its own in a few hours. Levodopa dyskinesias follow a short-duration pattern and do not persist beyond a few hours at most. She shouldn't take any more carbidopa/levodopa until the dyskinesias are resolved. If they are severe, I would suggest a glass or two of milk or some other source of protein. The digested protein products compete with levodopa and tend to block it from getting into the brain. However, bear in mind that if you overdo it with protein, the next dose of carbidopa/levodopa may not kick in.

 Levodopa short-duration responses tend to be all or none. Therefore, you may think of these responses in terms of thresholds. This is illustrated as separate thresholds for both the antiparkinson effect (improvement) and dyskinesias. With this type of response, the levodopa dose should be adjusted so that the peak brain levodopa level surpasses the improvement threshold but is less than the dyskinesia threshold. If your parkinsonism is well controlled but you inadvertently take extra levodopa, the higher brain levodopa level may then exceed the dyskinesia threshold, resulting in involuntary movements.

 Mrs. Quimby: "Half my doses of carbidopa/levodopa don't kick in. I take it every two hours. What should I do?"
 There are two common reasons for this problem. First, some of Mrs. Quimby's doses are undoubtedly close to meals, and dietary protein reduces the amount of levodopa that gets to the brain. Second, she may be taking a little less than an adequate dose; hence, some doses kick in and some do not. There are a variety of strategies for dealing with this problem. If this is due to meals blocking the levodopa effect, she could raise the carbidopa/levodopa dosage for the doses that fall around mealtimes. Alternatively, a dopamine agonist drug could be added.

 The walls of blood vessels in the brain have a natural barrier; this blocks many substances from entering the brain. This "blood-brain barrier" has transport sites for specific classes of biologic chemicals, including large neutral amino acids. L-dopa (levodopa) enters the brain via that specific transport site, along with other amino acids of this class. However, protein from the diet is digested into amino acids and these compete with levodopa for transport across this blood-brain barrier.

 Mr. Roberts: "I need to take a dose of carbidopa/levodopa every three hours to keep myself going. My total daily dose of levodopa is over 1500 mg. Is that too much?"
 For those experiencing short-duration levodopa responses, we will not worry about the number of doses or the total daily dose. Instead, we focus on each levodopa cycle; we want each dose to kick in optimally and last until the next dose takes effect. The goal is to maintain a continuous effect throughout the day. If 1500 mg (or even more) is required to do this, we won't fret about it.

The dosage and responses to sustained-release carbidopa/levodopa (Sinemet CR) are a little different from plain, immediate-release carbidopa/levodopa. This is illustrated by the following questions.

 Mrs. Star: "I take regular carbidopa/levodopa (immediate-release). The effect only lasts a couple of hours and sometimes it doesn't kick in at all. Would I do better switching to Sinemet CR?"
 Mrs. Star's response to carbidopa/levodopa is a bit erratic and doesn't last long (2 hours). With the sustained-release form, she could increase the interval between doses to three hours, but he should anticipate an even more erratic effect. She may do better sticking with the immediate-release formulation.

Mr.Teller: "I'm taking two 25-100 immediate-release carbidopa/levodopa tablets every four hours. I would like to switch to the sustained-release drug so that I wouldn't have to take it as often."
 There are rules for making this switch, allowing us to come up with a dose that is approximately equivalent in potency to what he is taking now. Subsequently further dose adjustment can be done to better fine-tune the response. First, we will derive the comparable dose of the sustained-release formulation. The individual sustained-release doses need to be 30-50 percent greater, compared to the immediate-release form. Currently Mr. Teller takes two 25-100 tablets, providing 200 mg levodopa.

Increasing that by 30 percent would translate into a 60 mg increment (i.e., 260 mg); increasing it by 50 percent would raise the dose by 100 mg (total of 300 mg). Thus a sustained-release dose between 260-300 mg would be appropriate. If he is often on the overdosed side, consider 2 ½ of the 25-100 sustained-release tablets, each dose (250 mg is as close as we can get to 260 mg). Alternatively, he could go with the higher dose of three 25-100 tablets (300 mg each dose).
 

How frequently should he take this? Since he currently takes the immediate-release drug at four-hour intervals, he could take the sustained-release drug every five hours. This may result in one less dose per day. Note that supplementary medications would have been another alternative, such as adding a dopamine agonist drug or a COMT inhibitor drug to produce a longer effect.

Mrs. Usher: "I switched to Sinemet CR a year ago. I can't seem to get a consistent effect. I take one 50-200 tablet every four hours. How can I switch back to the regular carbidopa/levodopa (immediate-release) tablet?"
 When switching from the sustained-release drug, you need less levodopa, since the immediate-release drug is completely absorbed. The dose of immediate-release levodopa needs to be about 2/3 to ¾ of the sustained-release dose. This is not an exact science, and thus we will approximate and come up with 150 mg of immediate-release levodopa (compared to the current 200 mg of sustained-release).
 

How often should she take this? The immediate-release drug lasts about 60-90 minutes less than the sustained-release form. More often than not, the 60 minutes is closer to the correct interval. Hence she could reduce the interval between doses from the current four hours, to every three hours. This will require an extra dose or two each day.

What if your levodopa off-state traps you at the shopping mall or movie theater? The following cases illustrate treatment strategies for that problem.

Mr. Vivien: "I love to go to baseball games. However, I've quit going because I usually get stuck in a frozen state and can't get out of my seat."
 Doing first things first, we should make certain Mr. Vivien has followed guidelines for optimizing his medications. Is his carbidopa/levodopa dose and dosing interval adjusted to give him the best effect? Would he benefit from a supplemental drug such as a dopamine agonist or entacapone? Also, is he aware of the effect meals can have on his levodopa response? For example, if he ate a couple of hot dogs at the game, they contain enough protein to turn off his levodopa response.
 

Assuming he has addressed all of these issues and is still at risk for immobile levodopa off-states at the game, we can then focus on rescue therapy. There are two options: liquefying his carbidopa/levodopa, and apomorphine. Their use is illustrated in the next example.

Mrs. Wallaby: "My medicine sometimes quits working without any warning. If I'm at the store, I'm stuck!"
 One quick way to restore mobility is to dissolve the usual carbidopa/levodopa dose in a half to full can of soda pop. Drinking this will produce an on-response in about 20 minutes, allowing Mrs. Wallaby to get going again. This effect, however, will only last about an hour; hence, she will need to take her pills shortly after the liquefied carbidopa/levodopa starts working. An alternative is a subcutaneous injection of apomorphine. This comes in injection syringes that fit in your pocket or purse. Before using this, however, you and your doctor need to determine the appropriate apomorphine dose. This is done by observation in your doctor's office.