When and How to Start Levodopa in the
Treatment of Parkinson Disease
Mark M Lin* and Robert Laureno
Departments of Neurology, Medstar Georgetown University Hospital, USA
Submission: July 03, 2019; Published: July 31, 2019
*Corresponding author: Mark M Lin, Department of Neurology at Medstar Washington Hospital Center, Georgetown University Hospital, Medstar Washington Hospital Center, Washington, DC 20010, USA
How to cite this article: Mark M Lin, Robert Laureno. When and How to Start Levodopa in the
Treatment of Parkinson Disease. Open Access J Neurol
Neurosurg. 2019; 11(2): 555808. DOI: 10.19080/OAJNN.2019.11.555808.
Levodopa has been used in the treatment of Parkinson disease for half a century. It has been the most effective medical therapy for reducing the cardinal motor symptoms of resting tremor, bradykinesia and rigidity. However, long term use of levodopa can be complicated by dyskinesia and motor fluctuations. Levodopa Induced Dyskinesia (LID) afflicts as many as 40% of patients being treated for Parkinson disease . Over the last 30 years, neuroscientists and neurologists have investigated the pathophysiology and management of levodopa induced motor complications. These researchers have developed novel medications such as dopamine agonists, Catechol-O-Methyltransferase (COMT) inhibitors, monoamine oxidase B (MAO-B) inhibitors, and several different preparations of levodopa. Treatment strategies for management of motor fluctuations and LID include switching from an immediate release levodopa to a longer acting oral levodopa, adding adjunctive inhaled preparations of levodopa, and combining levodopa with a long acting dopamine agonist with or without COMT or MAO-B inhibitors. If motor complications remain severe, treatment can be enhanced by continuous infusion of levodopa gel into the jejunum or invasive treatments such as deep brain stimulation [1-3], All of these methods focus on the management of levodopa induced motor complications. None of the aforementioned approaches is aimed at reducing the emergence of these motor complications in the first place. Here we review the latter topic, prevention of levodopa induced motor fluctuations and LID.
Due to the frequency of long-term levodopa induced motor complications, there has been concern that the medicine is neurotoxic. As a result, in the 1980s and 1990s, it was common practice to delay usage of levodopa (levodopa sparing strategy) by starting treatment with a MAO-B inhibitor or a dopamine agonist. To address the concern about neurodegeneration and progression of Parkinson disease during levodopa therapy, the ELLDOPA trial (Earlier versus Later Levodopa Therapy in Parkinson Disease) was conducted . There were 3 levodopa treatment groups (daily total levodopa doses of 150mg, 300mg and 600mg). Unexpectedly, all three groups showed improved UPDRS total scores (the Unified Parkinson Disease Rating Scale) compared to placebo after 42 weeks of observation. The greatest improvement occurred in the patients who received the highest doses. This trial suggested that levodopa may have slowed clinical progression of Parkinson disease. In contrast to this clinical benefit, striatal dopamine transporter imaging data from the same study demonstrated dose related loss of dopamine transporter signal, a sign of accelerated neuron loss [2,4]. The clinical improvement was not consistent with the apparent neuronal loss.
The LEAP trial (Levodopa in Early Parkinson’s Disease) was conducted to investigate these contradictory findings, . Using a daily dose of levodopa 300mg over an extended period (80 weeks) of treatment and observation, a controlled study was performed. In an early start group, patients received 80 weeks
of levodopa treatment. In the delayed start group, patients
received treatment for the final 40 weeks of observation. In the
end, for the two groups there was no difference in UPDRS scores
and a quality of life measure, PDQ-39 (the Parkinson’s Disease
Questionnaire-39). The results of the ELLDOPA and LEAP studies
suggest that levodopa neither slowed nor hastened clinical
progression of Parkinson disease. Since there is no evidence that
delaying levodopa therapy is beneficial, the neurologist should
feel free to prescribe it in early Parkinson disease. However, we
should not forget the ELLDOPA trial data, showing that levodopa
taken three times per day for 40 weeks, resulted in reduced
dopamine transporter signal. This finding could mean that
there was increased dopaminergic neuron loss. Further study
is needed to determine whether the pulsatile administration of
levodopa causes loss of neurons.
Levodopa induced motor fluctuations and LID are believed
to be related to pulsatile dosing of, longer exposure to and
higher doses of levodopa [1,4,6-8], Giving levodopa three times
daily is the most popular method of treatment currently. This
dosing is pulsatile because the half-life (T1/2, 90 minutes) of
orally administered levodopa/carbidopa is very short, resulting
in rising and falling blood levels of levodopa.
c. Giving levodopa in a less pulsatile way, using multiple
small doses a day.
Sustained release or extended release preparations of
levodopa have been available since the 1990s, but they have
failed to reduce motor complications. Addition of entacapone
to levodopa/carbidopa has been shown to extend the T1/2 [9-
11]. However, this combination, given 4 times per day, failed to
reduce risk of LID compared to traditional levodopa/carbidopa
therapy in the STRIDE-PD study . Recently, higher doses of
carbidopa combined with levodopa and entacapone have been
shown to improve motor fluctuations which had emerged during
treatment . Whether this novel formulation of levodopa/
carbidopa/entacapone will reduce the development of motor
complications in early Parkinson disease has not been tested.
Methods that provide a continuous stable dose of levodopa
have been successful in decreasing motor complications.
Continuous intravenous levodopa and continuous intraduodenal
infusion have successfully reduced motor fluctuations
and LID in advanced Parkinson disease [13,14]. However,
these invasive approaches are difficult to justify as strategies
to prevent levodopa induced motor complications for patients
with early Parkinson disease. Another less pulsatile levodopa
delivery method is transdermal. This investigational approach
uses a novel liquid formulation of levodopa/carbidopa providing
continuous administration via a mini-pump.
A simple alternative method to avoid pulsatile drug levels
uses currently available levodopa formulations in frequent small
doses. This has been a successful strategy for avoiding motor
complications. Recently, we have published the first retrospective
cohort study using this approach. Development of LID was rare
not only in naïve patients initiated on levodopa treatment every 3
hours (6 doses per day), but also in those patients converted from
traditional therapy to 6 daily doses . Because there has been
no controlled study or other retrospective evidence supporting
this approach, this inconvenient method has not been widely
adapted. Currently, there is no consensus among movement
specialists about how to start levodopa. In our institute, most
movement disorder specialists prescribe levodopa 4-5 times
per day (personal communication). We hope that a prospective,
randomized clinical trial will compare the incidence of motor
fluctuations and LID in patients treated with traditional 3 times
daily dosing to patients receiving 6 times daily dosing.
Because levodopa has a short half-life, the administration of
the medicine 3 or 4 times daily results in pulsatile dopaminergic
stimulation, a known risk factor for motor fluctuations and LID.
Many novel medications have been used to try to help patients
with these complications. However, there has been little attention
to preventing levodopa induced motor complications. For many
years we have treated patients with less pulsatile levodopa
therapy (6 doses daily). Those patients, who have been willing to
follow this inconvenient regimen, have rarely developed LID or
motor fluctuations. Someday, improved levodopa formulations
may eliminate the need for frequent dosing. At present, the less
pulsatile method of treatment deserves further use and study.