Medical Community Stuck on Therapeutic Strategies That are Counter to Scientific Evidence
When I was asked to write a piece for this blog I thought of the many things that could be of interest to people with Parkinson and carers, and I came up with the subject title of my contribution. One of the advantages of having a prolonged experience dealing with patients from all over the world is that I have been frequently exposed to the therapeutic habits of colleagues with different degrees of expertise and awareness of the scientific basis that lend support to our medical decisions. I chose three topics that I believe provide an example of the involuntary mistakes that are often made and that have a significant impact on the quality of life of our patients.
a) Administration of levodopa three times a day and moreover in non-fixed intervals
Levodopa remains the gold standard of treatment for Parkinson’s disease and there are no drugs in the pipeline that will eventually replace it. Therefore it is, in my view, of paramount importance to use it in the most effective way and based on our knowledge of its pharmacological properties and limitations. Let us review the facts first:
Throughout the world, levodopa is usually indicated to be taken three times a day (t.i.d.) during the waking hours, and very often without instructing the patient on the need to adhere to a strict dosing interval. The question therefore is, “why is this wrong?” To answer this question we need to review the scientific facts, or, using the term that is applied to drug therapy based on scientific knowledge, “what is the evidence?”
Levodopa is a drug with a very short half-life, about 2 hours, which in simple terms means that its duration of action is indeed very short, and its concentration in plasma correlates to some extent with the concentration achieved in the brain where it produces its therapeutic benefit. We also know that its beneficial effect is produced by its conversion to dopamine in the brain; dopamine being the naturally occurring neurotransmitter that is deficient in the brains of people with Parkinson; therefore levodopa is used to restore dopamine deficiency. Under normal conditions, dopamine is produced by dopaminergic neurons and released in a rather stable and constant fashion to achieve its desired effect on the control of motor activity. Therefore, we should attempt, if possible, to restore stable concentrations of dopamine in the brain to resemble the physiological conditions.
We also know that unstable, fluctuating levels of levodopa, leading to variable concentrations of dopamine in the brain is one of the major factors leading to the development of motor complications developing after long-term treatment with levodopa, namely motor fluctuations (on/off) and dyskinesia (abnormal involuntary movements) There is ample evidence from experimental research that the more continuous the level of dopaminergic stimulation, the less chances of developing the biochemical or molecular changes that lead to the appearance of motor complications. Likewise, in clinical studies, it has been found that the presence of more pronounced peaks and troughs of levodopa plasma levels favors the development of dyskinesia (not only more severe, but at an earlier time).
In clinical practice, when patients are instructed to take levodopa t.i.d. during the waking hours (let us say from 8 AM to 10 PM or midnight), and moreover, when the patients are left on their own to decide the timing of each dose, we encounter patients that take levodopa either with 6 to 8 hours intervals, or concentrate the levodopa they receive during the first 8 hours or the day, or what is worse, take it at irregular intervals (e.g. first dose early in the morning, second dose at noon, and the third dose at bedtime!!!) Both schemes translate into prolonged intervals in which there is almost no detectable levels of levodopa in plasma and therefore absence of dopamine in the brain.
An additional factor that leads to the development of motor complications is the use of high doses of levodopa at the beginning of treatment, and those that adhere to the t.i.d. regime believe this is the best way to maintain these convenient low levels. However, with the available strengths of levodopa, using fractions of a tablet at 4 hour intervals and in four divided doses (q.i.d.) (8AM, 12PM, 4PM, and 8PM), it is possible to achieve both ends: regular, more stable levels of levodopa, and therefore of dopaminergic stimulation, while at the same time maintaining low doses of levodopa. Let me give you an example: a patient may start with 4 doses of 50mg/each (half a 100mg tablet) which add up to 200mg/day; if necessary the dose can be later on increased to ¾ of a tablet amounting to 75mg per dose with a total daily dose of 300mg, and finally to 4 doses of 100mg/each totaling 400mg/day. We know from the pivotal ELLDOPA study and from other clinical trials (STRIDE PD) that keeping the doses of levodopa under 500mg/day for as long as possible leads to less complications.
b) Use of controlled release formulations of levodopa in an attempt to control end-of dose deterioration or wearing-off
In the late 1980’s and early 1990’s, two controlled formulations of levodopa were introduced in an attempt to overcome the limitations of the short half-life of levodopa and with the ultimate goal of reducing the incidence of wearing-off (shortening of the duration of each levodopa dose) or to control already established on/off fluctuations. The FIRST study, a clinical trial using levodopa/carbidopa CR in comparison with standard levodopa/carbidopa in patients taking levodopa for the first time tried to demonstrate the advantages of using controlled release formulations. The results not only failed to demonstrate any superiority of levodopa/carbidopa CR over the standard formulation, (duration of effect was no different between the two formulations) but the low incidence of adverse events (presence of off time or dyskinesia) in both treatment arms observed in this study underscored the importance of using low doses of levodopa and in a tightly controlled dosing schedule.
Despite these results, many colleagues continue using these formulations under the false belief that they will provide more stable and longer acting effect. In addition, these controlled release formulations have a lower bioavailability (at the same dose they achieve lower plasma levels than the standard formulations) than standard levodopa and a longer latency to the kicking-in of the effect after the first morning dose. What are the consequences of this? When replacing standard levodopa for controlled release levodopa higher doses are necessary to achieve the same effect, and the patient may need a morning booster dose of standard levodopa for faster control of morning akinesia. Moreover, these formulations cannot be fractionated, thus preventing a more flexible dose titration. With the passage of time, those with more experience, and more aware of the evidence have restricted their use to control nocturnal or early-morning akinesia by giving them at bedtime or as a supplementary dose in the middle of the night.
c) Use of the triple combination (levodopa/carbidopa/entacapone) in patients receiving levodopa for the first time
With the advent of COMT inhibitors in the mid 1990’s, under the premise that by increasing the area under the curve (maintaining higher plasma levels of levodopa for a longer time) without increasing the maximum concentration of the drug, it was believed that the addition of these drugs would somehow smooth-out the profile of levodopa concentration in plasma, thus avoiding the peaks and troughs responsible for the development of motor complications (fluctuations and dyskinesia). To confirm this hypothesis, a clinical trial was designed comparing the effects of the triple combination (levodopa/carbidopa/entacapone [a COMT inhibitor]), designated the STRIDE PD study. In this study, patients receiving levodopa for the first time were assigned to either levodopa/carbidopa or the triple combination in a random and blinded fashion and controlled for 134 weeks for the appearance of dyskinesia. The results of this trial were just the opposite of what was expected by the authors.* Patients on the triple combination developed dyskinesia earlier and had dyskinesia more frequently than those on levodopa/carbidopa alone. In interpreting their results the researchers conducting this study concluded that patients on the triple combination actually were receiving proportionally higher levodopa levels (levodopa equivalents). They realized that the COMT inhibitor did in fact increase the maximum concentration of the drug; thus they had failed to achieve a more continuous, stable and smoother plasma concentration of levodopa. This study was published in 2010, despite that, there are still colleagues that initiate levodopa therapy with the triple combination. (*At the time of the study there was already scientific evidence showing that COMT inhibitors did not modify the fluctuating levels of levodopa).
I do hope that these three examples will help in raising awareness of the need to base our treatment strategies on existing scientific evidence and not on fashion or beliefs.
REFERENCES
Nutt JG. Continuous dopaminergic stimulation: Is it the answer to the motor complications of Levodopa? Mov Disord. 2007 Jan;22(1):1-9.
Parkinson Study Group (2004) Levodopa and the progression of Parkinson’s disease. N Engl J Med 351(24):2498–2508 25.
Block G, Liss C, Reines S, Irr J, Nibbelink D. Comparison of immediate-release and controlled release carbidopa/levodopa in Parkinson's disease. A multicenter 5-year study. The CR First Study Group. Eur Neurol. 1997;37(1):23-7.
Stocchi F, Rascol O, Kieburtz K, Poewe W, Jankovic J, Tolosa E, Barone P, Lang AE, Olanow CW. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann Neurol. 2010 Jul;68(1):18-27.
___________________________________________________________________________________________
Oscar S. Gershanik, MD was on the steering committee for the Fourth World Parkinson Congress in Portland, Oregon, was the Program co-chair for the Third World Parkinson Congress in Montreal, Canada and was a speaker the First World Parkinson Congress. He is presently Professor of Neurology and Scientific Director, Institute of Neuroscience, Favaloro Foundation University Hospital.
Ideas and opinions expressed in this post reflect that of the authors solely. They do not reflect the opinions or positions of the World Parkinson Coalition®