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Supplements The Case for Early Initiation of Monotherapies and Delayed Dopaminergic Therapy in Parkinson's Disea

Advanced Strategies for Treatment of Parkinson's Disease: The Role of Early Treatment

Michael W. Jann, PharmD

Parkinson’s disease (PD) is associated with significant patient disability and costs to the healthcare system. It is questioned whether early treatment may improve outcomes and delay disability. Early treatment relies on early diagnosis, which can be difficult to achieve because the diagnosis of PD is based on motor symptoms, is clinical in nature, and is complicated by potential presentation of nonmotor symptoms prior to motor symptoms. Economic analyses demonstrate that treatments other than levodopa may be cost-effective. The lack of correlation between Unified PD Rating Scale (UPDRS) outcomes and imaging studies of dopamine uptake may reflect the inappropriate selection of study end points, since activities of daily living scores may be more applicable than motor function scores. Levodopa, the standard therapy for motor control of PD and one of the most effective options, is associated with complications (a wearing-off effect) when used long term. Other therapies, including dopamine agonists and monoamine oxidase type-B (MAO-B) inhibitors, may limit the rate of dyskinesia relative to levodopabased regimens. It appears that early treatment with the MAO-B inhibitor rasagiline (1 mg), as compared with late treatment, delays the onset of worsened UPDRS score, especially the nonmotor activities of daily living subscore.

Am J Manag Care. 2011;17:S315-S321

Parkinson’s disease (PD) is a progressive neurodegenerative disease associated with motor dysfunction characterized by bradykinesia, and at least 1 of the following: resting tremor, muscle rigidity, and postural instability.1 Levodopa has been considered the standard therapy for PD due to its ability to control the symptoms of motor dysfunction.2 Levodopa is converted in the neuron by striatal enzymes to dopamine to increase brain dopamine levels and treat motor symptoms. Carbidopa inhibits the peripheral plasma breakdown of levodopa to enhance delivery to the brain.3 After initially experiencing benefit with levodopa, with continued treatment, patients may develop dyskinesia and other motor complications, as well as nonmotor adverse effects.2 Additionally, the beneficial effects of levodopa wear off over time and its effectiveness gradually diminishes. The complications and wearing-off of levodopa effectiveness will be experienced by as many as 50% of patients within 5 years of initiating therapy.3 A recent study found that early treatment was cost-effective when patients with PD were treated with a dopamine agonist or monoamine oxidase type B (MAO-B) inhibitor (from a United Kingdom payer perspective).4 Exacerbation of both motor and nonmotor complications of PD may lead to hospitalization, which is considered a major direct cost factor associated with PD. Parkinson’s disease -related loss of productivity accounts for 30% to 40% of major direct costs. In improving both economic and health-related patient outcomes in PD, it is worthwhile to examine the impact of early diagnosis and treatment.5,6

From an economic perspective, a study showed that preventing levodopa-induced complications and delaying the initiation of levodopa therapy may be an effective strategy.4 In this Markov model economic evaluation, data from 2 trials of dopamine agonists (rasagiline, pramipexole) in early PD were examined for effectiveness (time to levodopa and time to levodopa-induced dyskinesia), cost, and quality-adjusted life-years (QALYs). Rasagiline was found to reduce costs by 18% per patient over 5 years and demonstrated a 25% prolongation of time to levodopa and a 10% delay in onset of dyskinesia. Rasagiline also demonstrated a 5% gain in QALYs relative to pramipexole.4 Despite this apparent benefit of utilizing dopamine agonists in early PD to delay the need for levodopa, there is still much controversy regarding when and how to diagnose PD, as well as when to initiate treatment. The next section will provide a brief overview of early diagnosis.

Early Diagnosis

Parkinson’s disease is challenging to diagnose, since there are no well-established biomarkers to determine if the disease is present.7 From a diagnostic standpoint, there are 3 basic aspects to the disease: pathology, impairment, and disability. Pathology changes reflect alterations in dopaminergic and other transmitters, both nigrostriatal and throughout the brain. Impairment involves motor, cognitive, and autonomic dysfunction of PD. Disability reflects the changes in the motor and cognitive domains, and their impact on the patient. Symptom severity may be measured by tools such as the Unified PD Rating Scale (UPDRS), which measures motor dysfunction, or the Nonmotor Symptoms Scale (NMSS), which rates the frequency and severity of nonmotor effects of PD.1,7 The most frequently used scale in evaluating early treatment of PD is the total UPDRS scale, which also has subscales that score motor function, mentation, and activities of daily living.

From a diagnostic perspective, PD may present in a manner similar to dystonic tremor, drug-induced parkinsonism, vascular parkinsonism, multisystem atrophy, progressive supranuclear palsy, or corticobasal degeneration. There is no reliable diagnostic test for PD, so the diagnosis is clinical in nature and is made by identification of bradykinesia and at least 1 of the following: resting tremor, muscle rigidity, and postural instability. Confirmation of a PD diagnosis also involves exclusion of other disease and presence of at least 3 positive criteria, which include: unilateral onset, resting tremor, progressive disorder, persistent asymmetry affecting side of onset most prominently, excellent response to levodopa, severe levodopa-induced chorea, levodopa response for 5 years or more, or clinical course of 10 years or more.1,8 Interestingly, the nonmotor factors associated with PD may be present for up to 10 years before the diagnosis is made.9

Brain imaging techniques are used as an adjunct in establishing and monitoring brain pathology. Single photon emission computed tomography (SPECT), using a dopamine transporter radiolabelled ligand, is used to establish alterations in uptake of dopamine, but cannot differentiate PD from multisystem atrophy, progressive supranuclear palsy, and corticobasal degeneration. Magnetic resonance imaging (MRI) may be used to differentiate PD through various techniques, but its use is not widely accepted. Similarly, transcranial sonography and positron emission tomography (PET) are other options, with the latter scan being very expensive and limited in availability.7

Based on the aforementioned challenges in diagnosis of PD, early identification of this disease remains challenging. It is quite possible that by the time motor symptoms of PD develop to the extent that a diagnosis can be considered, the nonmotor symptoms may have been present for years. In this context, there is debate regarding whether treatment should be initiated immediately or delayed until greater motor functional disability presents.10 At the core of the debate is the question of whether it is worthwhile to begin levodopa (which is limited by eventual wearing-off effects) early in the disease process, before significant disability develops. Also being questioned is the effect of early initiation of a therapy other than levodopa on disease progression.11 The remainder of this article will examine the evidence surrounding early treatment of PD.

Early Treatment

Landmark randomized trials of early treatment in PD are summarized in the Table.11-19 Where possible, studies that included imaging biomarkers and clinical outcomes were included in order to determine disease progression and correlation of clinical and pathological findings. Studies where dopamine agonists were compared with levodopa to determine disease progression and the preferred initial treatment were also included. Finally, studies of MAO-B inhibitors versus placebo were included in order to determine the presence of an early treatment effect. The following sections summarize these results with respect to clinical and radiological outcomes.

Levodopa-Based Regimens

The Parkinson’s Study Group examined carbidopalevodopa at various daily doses (compared with placebo) in a 40-week, randomized, double-blind, placebo-controlled trial (Earlier versus Later Levodopa Therapy in PD; ELLDOPA) of 361 patients.11 Patients were diagnosed within 2 years of randomization and judged unlikely to require medication for symptoms of PD for at least 9 months. The evaluation was completed at 42 weeks (after a 2-week washout) and the total UPDRS scale was used to evaluate the primary end point. In the carbidopa-levodopa group, the UPDRS score improved in a dose-related fashion (Figure 1) and the improvement was retained for the duration of the study (although follow-up time was relatively short). In sharp contrast, the SPECT [123I] β-CIT uptake sub-study demonstrated a mean percent decline of [123I]β-CIT uptake (assessment of striatal dopamine-transporter density) that was significantly greater with carbidopa-levodopa (-4% to -7.2%) than with placebo (-1.4%; P = .036). Patients receiving the highest levodopa dose (carbidopa 150 mg and levodopa 600 mg per day) experienced more dyskinesia, hypertonia, infection, headache, and nausea than placebo. The results of these studies suggest that clinical/function-related benefits of levodopa compared with placebo did not translate into pathological improvement; however, accelerated loss of nigrostriatal dopamine nerve terminals was demonstrated.11

A more recent study, the Stalevo Reduction in Dyskinesia Evaluation in PD (STRIDE-PD), compared carbidopalevodopa with or without entacapone, a catechol-O-methyltransferase (COMT) inhibitor used to extend the plasma half-life of levodopa, administered 4 times daily.12 The prospective, randomized, double-blind study enrolled patients with PD who required initiation of levodopa therapy. At 134 weeks, the carbidopa-levodopa-entacapone group had shorter time to dyskinesia (P = .04) and increased frequency of dyskinesia (42% vs 32%; P = .02), which was more pronounced in patients receiving dopamine agonists at baseline. There was no difference in total UPDRS scores between the groups, but the incidence of myocardial infarction was 1.9% in the carbidopa-levodopa-entacapone group versus 0% in the carbidopa- levodopa group (P value not reported). These results indicate that addition of entacapone to carbidopa-levodopa is not warranted in early PD, and may actually be deleterious with the increased risk of myocardial infarction (which led to a labeling change for entacapone).12

Levodopa Compared With Dopamine Agonists

In the context of levodopa’s uncertain benefit in early PD and entacapone’s failure to improve outcomes through continuous dopamine delivery, it is useful to evaluate effects of dopamine agonists relative to levodopa. In a 5-year, prospective, randomized, double-blind study, ropinirole was compared with levodopa-benserazide (a decarboxylase inhibitor similar to carbidopa).13 Treatment prior to enrollment was limited to 6 weeks of levodopa or dopamine agonists. Only 47% of the ropinirole group and 51% of the levodopa group completed 5 years of follow-up; treatment-related adverse effects led to study withdrawal in 27% and 33% of patients in the ropinirole and levodopa groups, respectively. Time to dyskinesia was prolonged in the ropinirole group (hazard ratio [HR] 2.82; 95% confidence interval, 1.78-4.44; P <.001). Among study completers, the difference in the mean change in UPDRS activities of daily living subscale scores was not significantly different between the groups; however, the mean UPDRS motor subscale score favored levodopa (P = .008).

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