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From Medscape Neurology & Neurosurgery Parkinson's Disease Expert Column The Future of Levodopa Therapy for Parkinson's Disease 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. -------------------------------------------------------------------------------- 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 =========================================== 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. ===================================== Best, Bob ********************************************** Robert A. Fink, M. D., F.A.C.S., P. C. 2500 Milvia Street Suite 222 Berkeley, California 94704-2636 Telephone: 510-849-2555 FAX: 510-849-2557 WWW: http://www.rafink.com/ mailto:[log in to unmask] "Ex Tristitia Virtus" ********************************************* ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn