A new look at levodopa based on the Elldopa study

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Parkinson Diseases Handbook By Lianna Marie

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S. Fahn

Department of Neurology, Columbia University, New York, NY, USA

Summary. Levodopa has been the gold standard for Parkinson's disease (PD) therapy since it was successfully introduced in 1967. But in the years since then, after recognizing that levodopa often leads to the motor complications of wearing-off and dyskinesias, there have been debates among clinicians as to when levodopa therapy should be started. Delaying therapy was advocated for the purpose of delaying the development of these motor complications. This became more popular as the dopamine agonists became available. Although less potent than levodopa in ameliorating the symptoms of PD, they were much less likely to produce the unwanted motor complications, even though they had their own adverse effects. When it was recognized that dopamine, itself, might be a factor leading to the death of dopaminergic neurons through its contributing to the formation of oxyradicals, a new concern arose, namely that levodopa, through its conversion to brain dopamine, might add to the existing oxida-tive stress and possibly enhance neurodegeneration of dopaminergic neurons. Though widely debated and without definite evidence, this possibility was sufficient to make some clinicians have further reason to delay the start of levodopa therapy. The ELLDOPA study was created to test this hypothesis. The clinical component of the study failed to find an enhancement of PD symptoms after levo-dopa was withdrawn following 40 weeks of levodopa therapy. Rather, the clinical results indicated that the symptoms had progressed much less than placebo, and in a dose-response manner. This suggests that levodopa may actually have neuroprotective properties. The uncertainty that a 2-week withdrawal of levodopa may not have entirely eliminated its symptomatic benefit and the discordant results of the neuroimaging component of the ELLDOPA study have created even more uncertainty that levodopa is neu-roprotective. A survey of neurologists who treat PD patients showed that the vast majority of these clinicians do not believe levodopa is neuroprotective, and they remain concerned about the drug's likelihood of inducing motor complications. Thus, the ELLDOPA study failed to change the treating pattern of PD, and the clinicians require more convincing evidence of either neuroprotection or neurotoxicity of levodopa before they would alter their treatment approach.

The Fluctuating History of Levodopa in the treatment of Parkinson's disease

Following the discovery of striatal dopamine deficiency in Parkinson's disease (PD) by Hornykiewicz and colleagues (Ehringer and Hornykiewicz, 1960; Bernheimeretal., 1973), Birkmayer and Hornykiewicz (1961) injected small doses of levodopa (up to 150 mg) intravenously and reported a transient reversal of akinesia. Barbeau et al. (1962) also reported benefit with small oral doses of levodopa (200 mg). Subsequently, many other investigators using small oral or intravenous doses reported similar results in very brief communications (Friedhoff et al., 1964; Umbach and Bauman, 1964; Hirschmann and Mayer, 1964; Pazzagli and Amaducci, 1966; Bruno and Bruno, 1966). However, not every investigator reported benefit from such small doses of levodopa. Greer and Williams (1963) failed to find benefit in two patients after 1 gm of D,L-dopa orally. Aebert (1967) saw no benefit after 70 to 100 mg L-dopa intravenously, nor did Rinaldi et al. (1965) even with inhibition of mono-amine oxidase. Double-blind trials with low dosage levodopa also failed to provide benefit (Fehling, 1966; Rinne and Sonninen, 1968) using up to 1.5mg/kg of intravenous levodopa. McGeer and Zeldowicz in 1964 were the first to use high doses of D,L-dopa that were later found to be successful by Cotzias et al. in 1967. They used up to 5 gm per day in ten patients for several days, and in one patient, 3 gm daily for 2 years, but only two patients showed any objective improvement.

The breakthrough in establishing levo-dopa as a therapeutically useful drug was the report of Cotzias et al. (1967). They treated 16 patients with doses of D,L-dopa of 3-16 gm per day, building the dosage up slowly to avoid anorexia, nausea and vomiting, which had been the dose-limiting complications with previous investigators. They reported marked improvement in eight patients and less improvement in two others. Of the eight who received 12g/or more per day, seven showed marked benefit. Granulo-cytopenia was seen in four patients, and bone marrow examination revealed vacuoles in the myeloid cells in four of the 12 patients with bone marrow examinations.

Because of the hematologic problems and because D-dopa in not metabolized to form dopamine, Cotzias and his colleagues subsequently used L-dopa (1969), and these problems were no longer encountered. Yahr et al.

(1969) carried out the first double-blind study with high dosage levodopa. This and many subsequent reports showed significant improvement in approximately 75% of patients with parkinsonism. Although a complete reversal of symptoms is rarely obtained, akinesia and rigidity were generally most benefited, and many who had been unable to turn in bed or arise from a chair became able to do so. Tremor has a more variable response; sometimes it is eliminated by levo-dopa, and in other patients, the tremor is resistant. A number of other symptoms, including postural instability and speech disturbance, are typically unaffected by levodopa therapy, suggesting these symptoms are not solely due to dopamine deficiency. The introduction of levodopa therapy by Cotzias was a revolutionary treatment for PD, not just an evolutionary one.

The development of inhibitors of L-aromatic amino acid decarboxylase that do not cross the blood-brain barrier was the next major step. Carbidopa and benserazide are such peripheral decarboxylase inhibitors. When given with levodopa, they allow for a 4-fold increase in the effectiveness of a given dose because peripheral metabolism of L-dopa to dopamine is blocked. More importantly, these agents block the gastrointestinal side effects, which are due to peripheral dopamine acting upon the vomiting center of the area postrema, which is not protected by the blood-brain barrier. The combination of levodopa with carbidopa was commercially marketed under the trade name of Sinemet, to indicate without (''sine'') emesis. The combination of benserazide and levodopa is marketed under the brand name of Madopar.

Levodopa remains today the most powerful drug available to treat PD, and this drug is considered the ''gold standard.'' The absence of a robust response to high-dose levodopa essentially excludes the diagnosis of PD and suggests there must be another explanation for the parkinsonian symptoms. In contrast, a marked and sustained response strongly supports the diagnosis of PD (Marsden and Fahn, 1982). Although numerous other treatment options are available in early PD when the disease is mild, virtually all patients will eventually require levodopa therapy as the disease worsens.

Early in the course of the disease, levo-dopa provides a long-duration response that can last several days even if levodopa is discontinued. This continuous response occurs in the presence of a short plasma half-life of a little more than 30 minutes (Muenter and Tyce, 1971; Tolosa et al., 1975).

As PD worsens (or with long-term usage of levodopa), more serious and persistent complications, such as ''wearing off'' fluctuations and dyskinesias (abnormal involuntary movements) emerge; these motor complications affect 75% of patients after 6 years of levodopa therapy (Fahn, 1992). These problems markedly impair the quality of life and functional status of affected patients, and prove challenging not only for the patient, but also for the treating physician. Today, these motor complications, especially clinical fluctuations and abnormal involuntary movements (dyskinesias), have limited the usefulness of levodopa. In fact, this has led many clinicians to consider a dopa-sparing strategy, using instead dopamine agonists, monoamine oxidase inhibitors, amantadine, and anticholinergics in the milder stages of disease, especially in younger patients who are more prone to develop these motor complications (Quinn, 1994; Fahn, 1998, 1999; Montastruc et al., 1999). The dopa-sparing strategy became more popular as the dopa-mine agonists became available. Although less potent than levodopa in ameliorating the symptoms of PD, they are much less likely to produce the unwanted motor complications, even though they have their own adverse effects profile (Rascol et al., 2000; Parkinson Study Group, 2000).

Early in the evolution of developing a treatment strategy for PD - in the early

1970s - I had advocated using levodopa early in the course of the disease as an attempt to spare dopaminergic neurons from overworking to produce more endogenous dopamine. However, half a decade later, I reversed my opinion and advocated the strategy of delaying the introduction of levodopa to avoid an early onset of wearing-off, on-off and dyskinesias (Fahn and Calne, 1978) as these motor complications were becoming increasingly common with high dosage levo-dopa therapy. Since 1980 there have been continual debates at neurology meetings and in the literature about whether to start levo-dopa early or late (Fahn et al., 1980; Hoehn, 1983; Muenter, 1984; Fahn and Bressman, 1984; Melamed, 1986; Markham and Diamond, 1981,1986; Caraceni, 1994; Quinn, 1994; Montastruc et al., 1999; Weiner, 1999; Factor, 2000; Montastruc, 2000). These debates mostly centered around the higher degree of clinical benefit seen with levodopa compared with other anti-PD medications versus the risk of developing motor complications that were particularly due to levodopa and not other medications. In double-blind clinical trials directly comparing starting treatment with levodopa or one of the dopa-mine agonists, pramipexole and ropinirole, levodopa was statistically significantly more likely than the agonists to induce both motor fluctuations and dyskinesias (Parkinson Study Group, 2000, 2004a; Rascol et al., 2000).

In 1983 a new element was added to the debate. In that year Cohen (1983, 1986) reported that oxyradicals produced by dopa-mine would cause oxidative stress in dopami-nergic neurons and could contribute to their degeneration, leading to the developing of PD. Cytosolic dopamine can be autoxidized to produce dopamine quinone and enzymati-cally oxidatively deaminated by monoamine hydroxylase to produce hydrogen peroxide, which in turn can lead to oxyradicals. Oxida-tive stress contributing to the pathogenesis of PD has much support, including postmortem biochemical evidence (Fahn, 1989; Fornstedt et al., 1990; Olanow, 1990, 1992; Jenner, 1991, 2003; Jenner et al., 1992; Fahn and Cohen, 1992; Zigmond et al., 1992; Spencer et al., 1995; Alam et al., 1997; Jenner and Olanow, 1998). Debates now include the potential of levodopa to enhance the progression of PD when considering whether levodopa should be started later rather than earlier.

The results of many in vitro studies have suggested that levodopa may be injurious to dopaminergic neurons (see reviews by Fahn, 1996, 1997). These findings have raised concerns that chronic levodopa exposure might hasten disease progression in PD patients. Accordingly, some physicians and patients have opted to defer the use of levodopa for as long as possible (Fahn, 1999). Others phy sicians have continued to use levodopa as first-line therapy, arguing that it is inappropriate to withhold the most potent symptomatic treatment for PD in the absence of clinical evidence of toxicity (Agid, 1998; Weiner, 1999; Factor, 2000).

Has the ELLDOPA study changed the way we perceive of levodopa therapy?

Because of the ongoing controversy about whether levodopa is toxic, a large, multicenter, randomized controlled clinical trial comparing three different doses of levodopa with placebo treatment in patients with early PD (the ELLDOPA study) was designed to answer this question (Parkinson Study Group, 2004b). This was a double-blind, pla

CHANGE IN UPDRS FROM BASELINE TO WEEK-42

CHANGE IN UPDRS FROM BASELINE TO WEEK-42

Elldopa Study

Placebo

- 150mg-300mg

600mg

Fig. 1. Changes in Unified Parkinson's Disease Rating Scale (UPDRS) from baseline to Week-42 in the ELLDOPA study. The changes in subjects treated with levodopa at different dosages or with placebo were determined on the basis of the total score of UPDRS. The scores were obtained by the blinded treating investigator who performed the evaluations before the morning dose of the daily dose of the study drug. The points on the curves represent mean changes from baseline in the total scores at each visit. Improvement in parkinsonism is represented by lower scores, and worsening by higher scores. Negative scores on the curves indicate improvement from baseline. The bars indicate standard error. Reproduced from Parkinson Study Group (2004b) with permission from the Massachusetts Medical Society (# 2004)

Placebo

- 150mg-300mg

600mg

Fig. 1. Changes in Unified Parkinson's Disease Rating Scale (UPDRS) from baseline to Week-42 in the ELLDOPA study. The changes in subjects treated with levodopa at different dosages or with placebo were determined on the basis of the total score of UPDRS. The scores were obtained by the blinded treating investigator who performed the evaluations before the morning dose of the daily dose of the study drug. The points on the curves represent mean changes from baseline in the total scores at each visit. Improvement in parkinsonism is represented by lower scores, and worsening by higher scores. Negative scores on the curves indicate improvement from baseline. The bars indicate standard error. Reproduced from Parkinson Study Group (2004b) with permission from the Massachusetts Medical Society (# 2004)

cebo-controlled, parallel group, multicenter trial of patients with early PD who had not been previously treated with symptomatic therapy. A total of 361 patients were enrolled, and were randomized equally to receive treatment with low- (150mg/day), middle- (300mg/day), or high- (600 mg/ day) dosage levodopa, or placebo. After forty weeks of treatment, the subjects underwent a three-day taper of their medications, followed by a two-week washout period during which they received no treatment for their PD. The primary outcome measure was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between baseline and after the washout period at Week-42. The goal of the study was to determine whether levodopa treatment affects the rate of progression of PD.

At the end of the two-week washout period, the UPDRS scores of patients treated with all three doses of levodopa were lower (better) than those of the placebo-treated group, in a dose-response pattern (Fig. 1). These findings suggest that levodopa is not neurotoxic, and may even be neuroprotective, though the possibility that patients were experiencing a longer duration of symptomatic response to levodopa that had extended beyond the two-week washout period could not be excluded. The highest dosage of levo-dopa was, however, associated with a statistically significantly higher incidence of motor complications, including dyskinesias (16% in the highest dose group) and a trend to develop the ''wearing off'' phenomenon.

In addition to the clinical data, a subset of patients in the ELLDOPA trial was also evaluated with b-CIT SPECT imaging, which (b-CIT binds to the dopamine transporter, DAT) was used as a marker for intact nigro-striatal dopaminergic neurons. These neuroi-maging studies showed that there was a larger decrease in striatal DAT binding in patients treated with levodopa, in a dose-response pattern (Fig. 2). Thus, these results are discordant with the clinical results. In contrast with the clinical data, the imaging findings suggest that levodopa may hasten the progression of PD. However, it is possible

SPECT SCAN RESULTS IN ELLDOPA

Subjects with Low Putamen < 3.25 (n=116)

Percent change in striatal ß-CIT uptake from baseline to 40 weeks of treatment

F

-1.4

h-

-6.0

-4.0

W

-7.2

1

n

/T

/T

V

Placebo 150 mg/d 300 mg/d 600 mg/d P (vs. Placebo) 0.17_04_0.015

Placebo 150 mg/d 300 mg/d 600 mg/d P (vs. Placebo) 0.17_04_0.015

Fig. 2. Percent changes in striatal binding of ß-CIT binding using SPECT from baseline to Week-40 in 116 subjects with low putamen binding (< 3.25) at baseline in the ELLDOPA study. The bar graphs reveal the percent reduction in ß-CIT binding from baseline to Week-40 when subjects were taking the highest assigned dosage of study drug. Data from Parkinson Study Group (2004b)

that the observed changes in the levels of uptake of this marker reflected a pharmacological effect of levodopa on DAT activity, rather than evidence of injury to dopaminer-gic neurons.

Thus, intriguing as the results of the ELLDOPA study are, it remains unclear whether levodopa may (either positively or negatively) affect the natural history of PD. Based on the clinical results, which indicate that a dosage of at least 600mg/d of levo-dopa would be most likely to slow the progression of PD, it would be logical for physicians to now consider starting therapy with this dose. However, the uncertainty whether a 2-week washout was sufficient to eliminate the symptomatic effect of levo-dopa, the discordant result from the imaging component of ELLDOPA, and that the dosage of levodopa is important in the development of motor complications, it is reasonable to customize the dose of levodopa to fit the specific needs of each patient.

The question as to whether knowing the results of the ELLDOPA study would influence physicians' treatment strategy was addressed in a survey (Fahn and Mazzoni, 2006). The results showed that no physician would start levodopa at 600mg/d and most would require a definite proof that levodopa slowed the rate of progression by at least 50% in order to start with this dosage. The concern of levodopa's known likelihood to induce motor complications is the primary reason for not altering treatment patterns for most clinicians. It is interesting that the results of ELLDOPA did not convince physicians that levodopa is neuroprotective. Eighty-eight percent of both those who were aware or not aware of the results of ELLDOPA believed that levodopa is not neuroprotective. This is most likely the main factor that prevents physicians from starting treatment of PD with levodopa. It is clear from this survey that we need to establish with a high degree of certainty that 600mg/d of levodopa slows the rate of progression before subjecting pa tients to the motor complication risks of such a dosage. This would require a different type of clinical trial design, the so-called delayed-start design (Leber, 1997).

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Author's address: S. Fahn, MD, Neurological Institute, 710 West 168th Street, New York, NY 10032, USA, e-mail: [email protected]

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