The Future of Levodopa Therapy for Parkinson's Disease

From Medscape Neurology & Neurosurgery

Parkinson's Disease Expert Column
Posted 09/22/2003

Robert A. Hauser, MD, MBA, Kelly E. Lyons, PhD, Rajesh Pahwa, MD

Introduction
Levodopa, the chemical precursor of dopamine, has been used in the treatment
of Parkinson's disease (PD) for more than 30 years. Despite the development
of several new medications for controlling PD symptoms, levodopa remains the
most efficacious treatment. Levodopa has been combined with peripheral
decarboxylase inhibitors, such as carbidopa, to reduce the incidence of
nausea.

Compared with dopamine agonist medications, levodopa achieves therapeutic
dose levels in a relatively short time, with simple dosing and fewer
short-term adverse effects, such as hallucinations, somnolence, and pedal
edema.[1] The major disadvantage of long-term use of levodopa is that the
patient may develop motor fluctuations and dyskinesias.[2,3] Motor
complications occur in PD because of both disease progression and levodopa
pharmacokinetics. The half-life of levodopa, when administered with
carbidopa, is approximately 90 minutes.

Pathophysiology of Motor Fluctuations
Before individuals develop clinical symptoms of PD, they already will have
lost 50% to 60% of nigrostriatal dopamine neurons, with a corresponding
reduction of approximately 70% to 80% in striatal dopamine concentration.[4]
Normally, dopamine neurons release dopamine in a relatively constant manner.
In early disease, surviving neurons are still able to take up levodopa,
store it as dopamine, and slowly release it over time in a continuous
fashion. As the disease progresses, more dopamine neurons die and this
"buffering capacity" is lost.[5]

Clinically, patients begin to notice that the beneficial effects of levodopa
last a few hours and then diminish (wearing off motor fluctuations). As more
dopamine neurons are lost, a patient's clinical response more closely
mirrors fluctuations in blood levodopa concentrations. Ultimately, the
beneficial response to levodopa may last 1 or 2 hours and then wear off. In
addition, with the loss of the buffering capacity, postsynaptic dopamine
receptors are exposed to fluctuating dopamine concentrations. These
fluctuations appear to cause a receptor sensitivity that is expressed
clinically as twisting, turning movements called dyskinesias. When
levodopa-derived brain dopamine is "too high," the patient experiences
dyskinesias, and when the brain dopamine concentration is "too low," PD
symptoms return. This creates a therapeutic window that progressively
narrows over time. Once a patient exhibits dyskinesias and motor
fluctuations, the addition of more dopamine medication will increase
dyskinesias; a reduction in dopamine medication will increase "off" time,
wherein PD symptoms return.

Preventing Motor Fluctuations and Dyskinesias
Potential strategies to prevent the development of motor fluctuations and
dyskinesias in patients with PD include using medications that would slow or
stop the progression of the disease or using symptomatic medications that
have longer half-lives, thereby preventing pulsatile stimulation of
postsynaptic receptors. Another possibility would be to deliver levodopa to
the brain in a more continuous fashion. Thus far, no medication has
definitively slowed or stopped the progression of PD, although several
medications are under investigation.

Continuous Dopaminergic Stimulation (CDS)
The CDS hypothesis suggests that symptomatic treatment strategies that
provide more continuous dopaminergic stimulation can curtail the emergence
of motor fluctuations and dyskinesias. Studies have shown that initial use
of dopamine agonists with relatively long half-lives can delay the onset of
motor fluctuations and dyskinesias. Investigations have demonstrated that
using long-acting dopamine agonists to treat PD symptoms in
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates results
in a lower incidence of dyskinesias than using levodopa .[6,7] On the basis
of these primate studies, several clinical trials have been conducted to
compare the initial use of dopamine agonists with levodopa in patients with
early PD.[2,3]

Dopamine Agonist Studies
Ropinirole is a long-acting dopamine agonist with a half-life of
approximately 6 hours. In a 5-year study,[2] 268 de novo PD patients were
randomized to receive levodopa or ropinirole as initial therapy. Additional
levodopa could be administered for better symptomatic control in either
group, as required. PD symptoms improved in both groups, but the benefit was
significantly greater for patients in the levodopa group. However,
significantly more patients in the levodopa group developed dyskinesias
(45%) than in the ropinirole group (20%). Adverse effects, such as
hallucinations, somnolence, and peripheral edema, were more common in the
ropinirole group.

Another study -- this one using the long-acting dopamine agonist pramipexole
-- produced similar results.[3] In this 2-year trial, 301 patients with
early PD who required dopaminergic therapy were randomized to receive either
pramipexole or levodopa, to which additional levodopa could be added, if
necessary. At 2 years, patients assigned to receive levodopa demonstrated
greater improvement in motor function than did patients assigned to receive
pramipexole. However, 51% of patients taking levodopa developed wearing off,
dyskinesias, or on-off motor fluctuations, compared with 28% of patients
taking pramipexole. Short-term adverse effects were higher in the
pramipexole group than in the levodopa group.

Both of the above-mentioned clinical trials demonstrated that initial use of
a long-acting dopamine agonist, to which levodopa could be added, caused
fewer motor fluctuations and dyskinesias. Furthermore, these studies showed
that the MPTP primate model of PD is predictive of what occurs in PD
patients, and the results are consistent with the CDS hypothesis.

Continuous Levodopa Administration
Another strategy for providing CDS is to administer levodopa in a more
continuous fashion. If this could be achieved, motor complications might be
avoided, while at the same time providing greater symptomatic benefit and
causing fewer short-term side effects than dopamine agonists. In patients
with motor fluctuations and dyskinesias, experience has demonstrated that
continuous enteral infusion of levodopa provides more continuous plasma
levels, compared with oral doses, and results in reductions in both off
periods and dyskinesias.[8] However, providing levodopa by continuous
enteral infusions is very impractical for PD patients, especially in early
disease.

Other potential strategies involve administering smaller levodopa doses
closer together or using the controlled-release formulation. However, both
of these strategies have been found to be associated with high variability
of levodopa blood concentrations and do not seem to provide continuous
dopamine stimulation.[9]

Catechol-O-methyltransferase (COMT) Inhibitors
Another strategy for providing CDS is to prolong the half-life of levodopa
through the addition of a COMT inhibitor, such as entacapone. Entacapone is
a peripheral COMT inhibitor that reduces the peripheral catabolism of
levodopa, thereby increasing its half-life to approximately 2.25
hours.[10-12] Thus, a greater amount of levodopa is delivered to the brain
over a longer time period. In PD patients with motor fluctuations, the
addition of entacapone to levodopa therapy results in reductions in off
periods.[13,14] At the same interdose interval, levodopa blood
concentrations fluctuate less with levodopa/carbidopa plus entacapone than
with levodopa/carbidopa alone, which raises the possibility that initiation
of entacapone at the same time that levodopa is introduced could provide CDS
and reduce the development of motor complications.

Using the MPTP primate model, Jenner and colleagues[15] compared
levodopa/carbidopa with levodopa/carbidopa plus entacapone. Administration
of levodopa/carbidopa on a 3-hour dosing schedule (4 administrations per
day) resulted in rapid induction of severe dyskinesias. However, when
levodopa/carbidopa (at the same dose and on the same schedule) was
administered with entacapone, significantly less dyskinesia occurred, with
comparable improvement in parkinsonian signs.

The study by Jenner and colleagues provides strong support for the CDS
hypothesis because the same agent (levodopa) was demonstrated to cause fewer
dyskinesias when administered in a more continuous way (with entacapone). In
addition, the study suggests that use of entacapone starting at the time
levodopa is introduced should curtail the emergence of motor complications
in PD patients. Clinical trials to definitively evaluate this are now in
development. Important considerations include the optimal dose and interdose
interval required to achieve CDS.

CDS in Clinical Practice
To maximize the use of CDS in clinical practice, young PD patients might be
treated initially with a dopamine agonist, and when the agonist alone is no
longer sufficient to control symptoms, levodopa/carbidopa plus entacapone
could be added. For patients who are not good candidates for dopamine
agonists (eg, older individuals and those with cognitive impairment),
levodopa/carbidopa could be used together with entacapone from the time
symptomatic treatment is first required.

The concurrent use of levodopa/carbidopa plus entacapone is now facilitated
by the availability of a levodopa/carbidopa/entacapone combination
product.[16] It is available in 3 dose combinations: 50 mg levodopa/12.5 mg
carbidopa/200 mg entacapone, 100 mg levodopa/25 mg carbidopa/200 mg
entacapone, and 150 mg levodopa/37.5 mg carbidopa /200 mg entacapone. The
combination product provides greater convenience than using separate
products because fewer pills are required. In addition, the 2 lower-dose
tablets are smaller than entacapone tablets, and the combination product is
less expensive than purchasing the products separately.

Thus, the levodopa/carbidopa/entacapone combination product can be used when
levodopa is first required to improve PD symptoms. Similar to
levodopa/carbidopa, the triple combination product should provide the
greatest symptomatic benefit with the fewest short-term side effects. In
addition, preclinical evidence suggests that this triple combination should
provide the additional benefit of causing fewer motor complications over the
long term.

Robert Hauser, MD, MBA, Director, Parkinson's Disease and Movement Disorders
Center; Departments of Neurology, Pharmacology, and Experimental
Therapeutics, University of South Florida and Tampa General Healthcare,
Tampa, Florida

Kelly Lyons, PhD, Research Associate Professor, Department of Neurology,
University of Kansas Medical Center, Kansas City

Rajesh Pahwa, MD, Associate Professor of Neurology; Director, Parkinson
Disease and Movement Disorder Center, University of Kansas Medical Center,
Kansas City


Disclosure: Dr. Hauser has disclosed that he has served on the advisory
board for Roche Laboratories, GlaxoSmithKline, Athena Neurosciences,
Pfizer/Pharmacia, Medtronics, Novartis, Teva Pharmaceuticals, Watson
Laboratories, and Somerset Pharmaceuticals. He has served as a consultant
for Roche, Somerset, Merck Germany, and Kyowa, and on the speaker's bureaus
of Roche, GSK, Athena Neurosciences, Pfizer/Pharmacia, Medtronics, Teva,
Novartis, and Somerset. Dr. Hauser has also served as an investigator for
Roche, GSK, Athena, Pfizer/Pharmacia, Medtronics, Novartis, Teva, Somerset,
and Kyowa. He has reported that he discusses the unlabeled uses of
levodopa/carbidopa/entacapone (Stalevo) and levodopa plus entacapone as
initial levodopa therapy in Parkinson's disease.

Disclosure: Dr. Lyons has disclosed that she has received grants for
educational activities from Medtronic.

Disclosure: Dr. Pahwa has disclosed that he has received grants for
educational activities and clinical research from, and has served as an
advisor or consultant for, Medtronic. He has had financial relationships
with Glaxo, Teva, Novartis, and Pharmacia.

Medscape Neurology & Neurosurgery 5(2), 2003. © 2003 Medscape