Author: Bill Stamey, M.D.

This fall I gave a pair of talks, one in Brewer, and another in Brunswick.  What follows is a summary of that information, or at least the heart of those discussions, which essentially amounted to a review of frequently asked questions on the topic of dopamine (DA).  I think understanding DA, and its pharmaceutical friend levodopa a little better might help people with Parkinson disease (PD) understand how the disease becomes a problem, and how and why certain medication regimens are needed.  I also hope this information sheds a little more light on the issue of why you should not adjust meds on your own, a topic I covered in the spring 2016 issue of MPDN (1).  Please read that article if you are a medication “self-adjustor.” 

The issue of medication self-adjustment comes up almost daily in my office, and should not be ignored because these medications can have good and bad results, depending on how they are used. 

I should also note that this article might not be for everyone. It requires some small consideration of brain biochemistry, of study data, and numbers. I will walk you through it, but some people will not want to do that sort of mental heavy lifting, and don’t use math as a language to describe nature.   If you are among them, and don’t want to read this article, I will give you this pearl:

Levodopa is a tool, and should be used properly.  If it is not abused, it is less likely to be a problem.  However, it does affect the brain, and should only be adjusted by a doctor, and even then might not be well tolerated.  Also, like any drug, if taken improperly, it is likely to lead to problems.

To understand these issues, you should know that one of the key factors  in PD is a deficiency of DA in the brain.  DA is used for many purposes, and when it runs low people may experience increased muscle tone (rigidity) and/or unwanted movements such as tremors.  This might seem obvious today, but it was not until the 1960s that scientists confirmed DA was depleted in PD.  After learning this fact, the first logical step in attempting to help was to give people with PD DA.  Giving DA by mouth was often unsuccessful because it caused nausea.  Because of this side effect, doctors attempted to give anti-nausea drugs, and this caused another problem.  Anti-nausea drugs usually block DA receptors in the brain, including the ones that DA is meant to target (footnote #1).  Giving drugs that act against each other was, and is, generally not a good idea.   And, because of this blocking effect, to get enough DA to the brain researchers would sometimes give what seem today like very high doses of DA.  Within a couple of years, patients exposed to these high doses began to show significant advances in their parkinsonism, which led many to ask whether DA was toxic.  It also meant finding another way to replace DA in the brain.

Scientists had learned some key points that were helpful in taking next steps.   Under normal circumstances DA is produced in the brain.  The building blocks of DA come from certain foods rich in proteins.   Eating those foods allows us to break the proteins down into smaller components called amino acids.  Our bodies recycle amino acids to make other proteins and neurotransmitters like DA.  One specific amino acid we get from eating proteins is tyrosine.  In the brain, tyrosine is converted into L-dopa, and L-dopa into DA.  Giving tyrosine alone did not help, and this further supported the idea that it was a breakdown in the production of DA that caused the deficiency. 

Under normal circumstances DA formation takes place in the midbrain (a part of the brainstem).  Specifically, DA is made in the midbrain’s substantia nigra, or “dark substance.”  It had been known since the 1950s that this dark substance was missing or depleted in people with PD; thus, researchers would learn this meant DA could not be formed.

In 1967 it was found that L-dopa could also improve parkinsonian symptoms because it could be easily converted by the brain into DA. Some people use the terms L-dopa and levodopa interchangeably. Levodopa is the international non-proprietary drug (generic) name of L-dopa.  

The finding that levodopa helped PD symptoms was an important breakthrough. However, the drug still might cause nausea in some patients because when it is taken by mouth it has to leave the GI tract and enter the bloodstream, where it will pass through the liver.  The liver contains an enzyme which can break levodopa down into DA, bringing us back to the nausea issue.   To fix that problem, the specific enzyme was identified, and a drug designed to block it: carbidopa.  It followed that carbidopa/levodopa was trialed in people. 

Carbidopa/levodopa was a revolutionary drug, which enabled people to live without some of the severe parkinsonian motor symptoms.   And, patients began to describe a phenomenon known as “ON” versus “OFF.” 

When a person feels ON there is a decrease or absence of some or all motor and nonmotor signs and symptoms of PD, such as tremor, stiffness, slowness, low energy, fatigue, and soft speech.  When a person is OFF, the signs or symptoms return.   

Before levodopa, PD patients would slowly and progressively develop the signs and symptoms of disease.  Many would become bed-, or wheelchair-bound, and succumb to the effects of wasting, deconditioning, clots in immobile limbs, infections, pneumonia, and so on.  There were wards in some hospitals dedicated to the long term care of these unfortunate patients.

At first, doctors did not know how to titrate the drug.  And, in those early days of the levodopa era, very large doses were routinely given.  It seemed appropriate to treat until symptoms were completely controlled. There were also many advanced patients, treated with dopamine for the first time, who seemed to require high doses.  Just as had happened with DA treatment, it did not take long for disease to seemingly progress, for levodopa to lose efficacy, and for scientists, patients, and doctors to question whether or not the drug might be at fault.  This question has never been fully eradicated from the literature, though many attempts have been made to settle the issue.

Several retrospective analyses have compared death and disability before and after the levodopa era (2-5).  In short, when numerous sources of data were pulled together it was found that before the levodopa era, in the first five years of disease over 25% of PD patients developed severe disability or died; whereas these devastating results occurred in less than 10% after the introduction of levodopa.  The numbers over time are even more telling.  With PD present up to 10 years death or severe disability was seen in over 60% of patients in the pre-levodopa era, and about 20% after.  By 15 years, over 80% of the pre-levodopa era patients were either severely disabled or dead; and under 40% after.  The bottom line is that life spans generally normalized, or at least become significantly prolonged after levodopa was introduced as a treatment because people had fewer and less severe complications of PD.  

Still, it was reported in the levodopa era that after about 5 years of treatment with levodopa up to 50% of patients developed what are known as motor fluctuations, meaning that function might not be so predictable or that medications might wear off too soon (6).  This end of dose wearing off phenomenon began to occur in 70% or more patients after 15 years of treatment, as did unpredictable fluctuations and dyskinesias (involuntary twisting-turning movements which are not tremors).  It was not clear at this time however, whether this was all due to progression of disease or levodopa.  Confusing matters, doctors began to use the term “levodopa-induced dyskinesias.”  It is true that virtually any person with PD will have dyskinesia temporarily if given too high a dose of levodopa. 

It is not clear whether levodopa over the long term causes dyskinesia.  It seems more likely the answer is that levodopa doesn’t, though there might be some exceptions, and more than a few caveats.  The issue is complicated.

Over the course of disease with PD as less DA is produced in the brain, more levodopa is needed.  Levodopa is converted to DA and stored in a part of the brain called the basal ganglia.  Early in disease the basal ganglia is able to store the large amount of DA the brainstem is able to produce. In this case, a person will usually take relatively low and infrequent doses to make up for a small deficit.  A little goes a long way.  However, over time less DA is produced in the brain and the basal ganglia is less able to store as much because of the progression of the disease itself.  People with PD lose those cells that store DA in the basal ganglia.  It could be thought of like a car that starts out with a large gas tank.  In this car analogy, the gas tank is slowly shrinking.  A car with a smaller gas tank has to make more frequent stops at gas stations to avoid running out of gas and shutting off. By the same analogy, a PD patient with a smaller basal ganglia storage has to take more frequent doses of levodopa.  This means ON time is shorter.  

Unfortunately, as disease progression goes forward, the threshold at which dyskinesia occurs becomes lower also.  This means that a person can no longer tolerate large doses of DA without experiencing involuntary movements.  When disease advances, taking smaller and more frequent doses of levodopa is one strategy for avoiding or minimizing dyskinesias and OFF time. Even with the best of treatment though, by the time of advanced disease many patients will have dyskinesia whenever they are ON.  The key is in minimizing the severity of dyskinesia and other issues. 

Because of the advent of dyskinesias in treated patients, since at least the 1980s major thought leaders in PD have debated about whether levodopa could safely be started early or late in the course of the disease (7,8).  After all, most of the time dyskinesias only occur in treated patients in the ON state.  This might lead one to conclude that it is the medication causing the problem.  Several studies suggested that dyskinesias could be predicted by high daily levodopa dose and longer duration of levodopa treatment.  Delaying the initiation of levodopa was thought by many to be the best therapeutic strategy to prevent motor fluctuations and dyskinesias.  Thus, the term “levodopa phobia” was coined, to refer to neurologists and patients who withheld the introduction of adequate levodopa therapy as long as possible (9).    And, in the 1980s other medications such as DA agonists were developed, which were able to stave off some of the motor symptoms of disease.  However, this class of drugs is not always tolerated in doses that would be needed to reach the same efficacy as levodopa.

In the 1990s researchers set out to settle the issue as to whether levodopa alters the natural history of PD, or whether levodopa hastens the loss of brain cells (neurodegeneration) in the ELLDOPA (Earlier vs. Later LevoDOPA in PD) trial (10,11).   This was a randomized, double-blind, placebo-controlled, parallel group, multi-center trial at 33 sites in U.S. and 5 sites in Canada. The study was designed to include 360 early, mild PD patients who had not previously required levodopa treatment, but were symptomatically ready to try medication. Patients were placed in different groups of three times daily dosing of: placebo, levodopa 50mg, levodopa 100mg, levodopa 150mg, and levodopa 200mg.  The primary outcome variable measured was a change in total Unified Parkinson disease Rating Scale (UPDRS) scores from baseline to 40 weeks after randomization, and after 14 days washout from meds (to see if there was a persistent effect) (footnote #2).  Patients who took higher doses of levodopa showed the most improvement in motor scores. Some of that data Is summarized here. 

 3 x daily dose    dyskinesia  (%)    wearing off (%)        

Placebo                        (3.3)                (13.3)

50                                  (3.3)                (16.3)

100                               (2.3)                 (18.2)

200                              (16.5)                (29.7)

The table shows that the 200mg three times daily group had the highest rate of dyskinesia (at least five times as much as the other groups), and considerably more wearing off at the end of the study. It would seem that early in disease 200mg three times daily might be too high and associated with earlier motor complications. However, it is also interesting to note that even the placebo group had some degree of dyskinesia, evidence that dyskinesia is part of the disease-though it can be exacerbated by medications (footnote #3).  A key insight from the ELLDOPA trial is that it is difficult to determine when an early dose of a drug such as levodopa is too high.  It takes a great deal of investigation to detect these nuanced issues. 

Later, the CALM-PD trial followed long term use of DA agonists (12).  Post-hoc analysis of this trial showed that the onset of dyskinesias was an expected complication of disease that was independent of when levodopa was started.

Other authors have suggested that cumulative levodopa dose (how much a person has taken in their life) may be an independent predictor of dyskinesias in patients with PD (13).  This line of reasoning has led many to believe they should delay starting levodopa, or that there is a “shelf-life” for taking levodopa.  They seem to believe there is a set number of years they can take levodopa before it “stops working.”  However, evidence favors starting levodopa when it is needed, though avoiding a too much, too soon approach.  Observations and trials such as the above-mentioned ELLDOPA study have shown that high doses of levodopa early in disease can result in early appearance of dyskinesia and possible irreversible advance of disease.  One of the problems with proving it is not the drug itself, but high doses of the drug, is that it would be unethical to design a study to test this idea in people.  However, in PD model rats treated with higher levodopa doses for short periods dyskinesias developed earlier than in rats treated chronically with lower doses, although the lower daily dose rats ultimately were given higher cumulative doses (14).  At least in rats, the cumulative dose hypothesis does not seem to fit and when levodopa therapy was started did not change the risk of motor complications.

Finally, in 2014 Italian researchers set out again to determine if starting levodopa early in disease had an effect on progression of PD (15).  Investigators went to Ghana, Africa, where they found 59 PD patients who for a variety of reasons had never tried levodopa, and an additional 32 patients who took low doses of the drug.   These patients were matched by age, sex, and disease duration with groups of Italians (2282, only 50 of whom had never tried levodopa).  Patients were followed over several years.  In both groups the average time it took for patients to develop medication failure was 5-6 years.  The average time to develop dyskinesia was 6-7 years.  The only group with early medication failure or dyskinesia were those who took high daily doses of levodopa.  Duration of time one had taken levodopa was not a risk factor.  However, duration of disease itself was a risk factor, as one would expect if these complications are also simply features of the disease.

  As if to illustrate these points, one patient with advanced PD of several years had dyskinesias with the first ever dose of levodopa.   

In summary, levodopa is the strongest, most effective drug available for the motor symptoms of PD.  It is a tool, and must be used properly.  If you have made it to the end of this article and are still a medication self-adjuster, you should know that the understanding of that proper use is complex, and not something that should be taken for granted. And, you should know that there is much more to the story, not discussed here. The science of brain DA and levodopa in PD are not easy data sets to follow. I cannot stress enough that medication adjustment is something best left in the hands of the specialist. Thus, as complicated as this article might seem, it only touches the surface of the secret life of dopamine. 

Footnotes: 

1. This is a bit of biochemistry and cell biology, but DA is sort of like a key, and the DA receptor is sort of like an ignition: one fits specifically into the other and has an activating effect.  It is one way brain cells communicate with each other, or get each other to do something, such as move a muscle in the body.   There are many different receptors in the brain that respond to specific neurotransmitters such as DA.    Another tricky detail is that there are subtypes of the DA receptor in different parts of the brain.   Each has a different set of functions.  
2. It was discovered in post-hoc analysis of this trial that a full washout would take 28 days.
3. In fact, dyskinesia can be seen with DA agonists of enzyme blockers used to treat PD.  Levodopa does not have to be involved.  And, when patients have deep brain stimulation the device itself may trigger dyskinesia. 

REFERENCES

1. Should you adjust your own Parkinson’s meds?  Spring 2016, MPDN
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10. Fahn S.  Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Earlier vs Later L-DOPA  Arch Neurol. 1999;56:529-535.
11. Parkinson Study Group. Levodopa and the progression of Parkinson’s disease. N Engl J Med. 2004;351:2498-2508.  
12. Constantinescu, et al. CALM-PD Investigatorsof the Parkinson Study Group, Impact of pramipexole on the onset of levodopa-related dyskinesias. Mov Disord 2007; 22: 1317–9.
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15. Cilia, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain.  2014;137(Pt 10):2731-42