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Supplements Implications of Early Treatment for Parkinson’s Disease [CME/CPE]

Early Pharmacologic Treatment in Parkinson's Disease

Robert A. Hauser, MD, MBA


Early treatment of Parkinson's disease (PD) affords an opportunity to forestall clinical progression. Levodopa is the most effective treatment for PD motor signs and symptoms, but its use is associated with the development of motor fluctuations and dyskinesias. Because of this, levodopa use is commonly withheld until the patient experiences functional disability. Other medications are available for the treatment of early PD and can be initiated at or near the time of diagnosis. Monoamine oxidase type B (MAO-B) inhibitors provide mild symptomatic benefit, delay the need for levodopa, are very well tolerated, and may provide long-term disease-modifying effects. Dopamine agonists provide moderate symptomatic benefit, delay the need for levodopa, and cause fewer motor complications than levodopa. Compared with levodopa, however, dopamine agonists cause more somnolence and sudden-onset sleep as well as impulse control disorders. The treatment of early PD depends in part on the individual patient's anticipated risk of side effects and the degree of motor improvement required. Physicians should also consider the early use of MAO-B inhibitors in light of their very good tolerability and the recent evidence suggesting long-term disease-modifying effects.

(Am J Manag Care. 2010;16:S100-S107)



The devastating impact of Parkinson's disease (PD) on the lives of patients is well known and widespread. Up to 1 million people in the United States are believed to have PD, with onset typically occurring in patients over the age of 50 years.1 For many years, first-line pharmacologic treatment of PD consisted of levodopa to increase brain dopamine concentrations. It is administered with a dopa decarboxylase inhibitor (DDI) to minimize adverse effects (eg, nausea) by limiting the peripheral metabolism of levodopa.2 Nevertheless, levodopa treatment is associated with significant adverse events, specifically motor fluctuations and dyskinesias (even when accompanied by a DDI), and is commonly withheld until functional disability emerges and the benefits of treatment outweigh the side effects. Delaying treatment, however, means that the potential benefits that may accrue as a result of early treatment, whether in terms of reducing symptoms or even slowing disease progression, are largely missed.

Emerging clinical trial data point to the potential of certain agents to delay functional symptoms and possibly slow the evolution of PD. Early treatment of PD offers the opportunity to forestall clinical progression.3 The implications of slowing disease progression are enormous, comprising additional time in the lives of PD patients in which symptoms are reduced and the descent into profound morbidity is, at least for a time, delayed. Early treatment of PD may decrease the costs of treatment with consequent effects on the economic burden to patients, families, and the larger society.4 The potential to reduce symptoms and the possibility of slowing disease progression is contingent upon an understanding of the relative benefits of pharmacologic therapies in the context of early PD treatment. The present article will review pharmacologic options for early treatment of PD and discuss the relevant clinical guideline recommendations.

Neuroprotection/Disease Modification

Ideally, early treatment of PD would confer a neuroprotective effect. Limited evidence has hinted at the possibility of a neuroprotective effect with several agents for the treatment of PD, but none have been definitively proven to possess such properties.

The notion of neuroprotection is distinct from that of disease modification in that the former implies an alteration of the pathophysiology of the disease, whereas the latter implies an effect upon clinical outcome without necessarily affecting the disease pathophysiology.5 That said, a definitive and clinically practical means of measuring neuroprotection remains an area of considerable debate. A slowed rate of neuron loss is the most accurate method of doing so, but this is not currently possible in PD.6

Secondary means of measuring neuroprotection involve applying clinical assessment instruments to evaluate the change in various domains of PD deterioration, including motor impairment, disability, and quality of life. Other potential markers for neuroprotection include time to a given event (eg, delay of levodopa initiation, death), radionuclide positron emission tomography (PET), or single photon emission computed tomography (SPECT).5,6 None of these approaches, however, have been validated as a reliable means of measuring neuroprotection.


The key clinical trial examining possible neuroprotective or disease-modifying properties of levodopa is the Earlier versus Later Levodopa Therapy in Parkinson Disease (ELLDOPA) study, conducted by the Parkinson Study Group.7 This was a randomized, double-blind trial in 361 patients with early PD. Patients received 1 of 3 doses of levodopa/carbidopa (150/37.5 mg, 300/75 mg, or 600/150 mg given in 3 divided doses) or placebo for 40 weeks followed by a 2-week washout period.7 The primary outcome of the study was change in Parkinson's severity from baseline to week 42, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS).7 A preplanned substudy was also conducted; at baseline and week 40, SPECT with radiolabeled 2betacarbomethoxy-3beta-(4-[125I]iodophenyl)tropane (ß-CIT) was used to determine the effect of treatment on dopaminetransporter density. ß-CIT uptake is a potential biomarker for dopamine neuronal status.

The results showed that treatment with levodopa was significantly better than placebo at reducing worsening of Parkinson's symptoms in a dose-dependent manner (Figure 1). Patients given placebo experienced a gradual worsening from baseline in UPDRS scores. All 3 levodopa doses were associated with rapid improvement; scores did not return to baseline values until approximately week 25 with the 150-mg dose, week 38 with the 300-mg dose, and week 41 with the 600-mg dose (ie, with the 600-mg dose, a week after cessation of therapy during which the UPDRS scores rapidly deteriorated).7 At week 42 (following a 2-week washout), patients in all 3 levodopa groups demonstrated significantly less (P <.001) worsening of symptoms from baseline to end point compared with those given placebo.

In apparent contrast to these results, the dopamine transporter substudy showed that patients given levodopa experienced a greater decrease in ß-CIT uptake than patients given placebo, a difference that was significant (P = .036) when 19 patients in the study who proved not to have a dopaminergic deficit were excluded.7 The implications of these data are uncertain. At face value, the clinical results are consistent with a neuroprotective effect of levodopa, but the imaging results suggest a possible neurotoxic effect. However, it is possible that neither of these 2 interpretations is correct. A 2-week washout of levodopa may be insufficient to resolve all symptomatic benefit (due to the "long-duration response"), and the difference in outcome between placebo and levodopa groups might disappear if the subjects were followed for a longer time. In addition, it may be that levodopa affects dopamine transporter imaging, either through a pharmacologic or compensatory mechanism, thereby rendering this imaging modality invalid as a measure of disease progression. Thus, it is possible that levodopa has no effect on the rate of progression of the underlying disease.

Dopamine Agonists

A limited number of studies have sought to evaluate possible neuroprotective effects of dopamine agonists in the treatment of PD. ß-CIT imaging was used in a subset of subjects participating in the CALM-PD (Comparison of the Agonist Pramipexole With Levodopa on Motor Complications of Parkinson's Disease) study, conducted by the Parkinson Study Group prior to the ELLDOPA study. This study in 82 patients with early PD compared initial treatment with pramipexole to initial treatment with levodopa/carbidopa.8 The primary outcome was change in SPECT-evaluated ß-CIT striatal uptake at 46 months. Disease severity was also evaluated using the UPDRS prior to each imaging interval when patients had been off the study drug for 12 hours.8 At 46 months, the rate of decline in ß-CIT striatal uptake was significantly less in the pramipexole group compared with the levodopa group; the decline from baseline was 16.0% versus 25.5%, respectively (P = .01)8 (Figure 2). However, at 22 months, patients assigned to initial treatment with levodopa had significantly better total and motor UPDRS scores than patients given pramipexole (P = .02 and P = .04, respectively). Significant superiority in UPDRS scores was no longer present at 34 months or 46 months.8

The REAL-PET (Requip as Early Therapy versus L-dopa- PET) study included 186 patients with early PD and compared the dopamine agonist ropinirole to levodopa over 2 years; the primary outcome was change in dopamine terminal function evaluated by PET imaging.9 At 2 years, the imaging data showed significant decline with ropinirole compared with levodopa.9 However, mean UPDRS motor scores worsenend by 0.70 from baseline to year 2 in the ropinirole group compared with an improvement of 5.64 in the levodopa group. Ropinirole also produced less dyskinesia and was associated with a longer time to the onset of dyskinesia.

The Parkinson's Disease Research Group of the United Kingdom (UK-PDRG) undertook a randomized, open-label trial in 782 patients with early PD that compared levodopa/DDI versus levodopa/DDI + the monoamine oxidase type B (MAO-B) inhibitor selegiline (deprenyl) versus bromocriptine over a study period of 5 years.10 The outcome measures were mortality, disability measured with both the Hoehn and Yahr scale and the Webster scale, and adverse events. Bromocriptine was associated with fewer motor complications compared with levodopa/DDI as well as levodopa/DDI + selegiline, but bromocriptine-treated patients returned to baseline disability scores approximately 3 years after initiating therapy, which was 1 year earlier than those treated with levodopa.10 Mortality rates were similar between groups.

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