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Supplements Best Practices for Treating Parkinson’s Disease: A Focus on Symptoms and Considerations for Manage
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Deborah F. Boland, DO, MSPT, and Mark Stacy, MD
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Early Treatment of Parkinson's Disease: Opportunities for Managed Care
Daniel L. Murman, MD, MS, FAAN
Participating Faculty: Best Practices for Treating Parkinson's Disease: A Focus on Symptoms and Considerations for Managed Care

Early Treatment of Parkinson's Disease: Opportunities for Managed Care

Daniel L. Murman, MD, MS, FAAN
A number of preclinical studies have offered evidence of neuroprotection from dopamine agonist agents, including pramipexole, ropinirole, and rotigotine.16-18 With regard to human clinical trials, the CALM-PD study, in a substudy within the larger trial, employed SPECT to evaluate disease progression by evaluating uptake of striatal 2β-carbomethoxy-3β-(4-iodophenyl)tropane(β-CIT), a marker for dopamine neuron degeneration, in 82 subjects with early PD receiving pramipexole or levodopa/carbidopa.19 At 4-year follow-up, pramipexole-treated patients experienced significantly greater β-CIT uptake decline versus levodopa-treated patients, and β-CIT uptake decline was significantly correlated with change in UPDRS from baseline. These data point to a possible modification of dopaminergic neuronal degeneration with pramipexole that is greater than that seen with levodopa (though levodopa also exerted positive benefits), although the effects of these medications on synaptic activity and β-CIT uptake are not fully understood.19

The REAL-PET study employed PET imaging to compare the effects of ropinirole versus levodopa in 186 patients with early PD over the course of 2 years.20 PET data revealed significantly slower disease progression with ropinirole treatment based on the rate of loss of dopamine-terminal function. However, motor score improvement, which was seen with both treatments, was sustained in the levodopa group but not the ropinirole group. Importantly, in terms of symptomatic effectiveness of treatment, reduced dyskinesia and longer time to dyskinesia were associated with ropinirole versus levodopa, although Clinical Global Impression scores were not significantly different between treatment groups.

One caveat that should be acknowledged with regard to early therapeutic intervention is the risk of additional side effects involved with starting drug treatment early. Certain drugs commonly used in PD—such as levodopa, anticholinergic agents, and dopamine receptor agonists—are associated with side effects as well as nonmotor symptoms that might exert their own effects on QoL and therapeutic adherence. That said, it may be the case that early treatment of PD confers other benefits—whether or not neuroprotection or outcome modification per se can be achieved—such as potentially enhancing effects on mechanisms that compensate for the deficits caused by PD. An analogy might be made to the concept of “cognitive reserve” in dementia, in which a built-in neurological resilience resists the deleterious effects of deterioration. Such a notion, while credible, has not been demonstrated to date, although, like neuroprotection, proof of such a concept is not easily achieved.

In addition to pharmacological therapies, nonpharmacological therapies such as physical therapy (PT) and exercise also offer opportunities for improving patient status in PD. While PT and exercise have been widely studied in PD, this is somewhat less true in early PD. One controlled trial from UCLA by Fisher et al, published in 2008, randomized 30 patients with early PD (Hoehn and Yahr stages 1 or 2) to 1 of 3 different interventions.21 The first intervention was high-intensity body weight–supported treadmill training, under the supervision of a physical therapist, for 24 sessions over a period of 8 weeks. The second intervention was a more traditional low-intensity PT approach to PD (eg, range-of-motion stretching, balance activities, resistance training), also for 24 sessions over 8 weeks. The third intervention was a series of 6 “zero-intensity” educational classes over 8 weeks, which addressed topics such as improving QoL, dealing with stress, improving memory, and advances in PD treatment. The authors found small improvements in UPDRS for all 3 groups in addition to gait and sit-and-stand improvements. However, the high-intensity group accrued additional significant benefits, including more robust and diverse improvements in both gait and sit-and-stand, and also a lengthening of cortical silent period (CSP) durations. This latter improvement is important since shortened CSP durations are believed to be indicative of the excessive cortical excitability characteristic of PD.

Cost Implications of Early Treatment

Total direct medical costs for PD in the United States have been estimated at $6.2 billion annually, and total costs have been estimated at $11 billion annually.22 O’Brien et al estimated direct annual per patient costs based on 4 patient categories: 1) a non-institutionalized chronic patient with an acute event possibly requiring temporary hospitalization (representing 23% of PD patients), with estimated direct costs of $16,610; 2) a chronic patient managed on an outpatient basis (54%), with direct annual costs of $3573 ($5363 if medical equipment and transportation are included); 3) an institutionalized patient (11%), whose annual costs are $47,807; and, 4) a patient who dies (12%), with associated direct annual costs of $3769.22

A number of cost-effectiveness studies have been undertaken to determine the economic value of early intervention for PD, and the results have been largely, if not unanimously, positive. For example, Haycox et al observed that early rasagiline treatment delayed onset of dyskinesia and levodopa initiation that were associated with cost savings over a 5-year study period.23 Noyes et al found that treatment with pramipexole in patients with early PD was associated with cost savings versus levodopa in patients with depression and low baseline QoL.24 Hoerger et al also found overall pramipexole to be cost-effective in patients with early PD despite initially higher drug costs.25

It must be acknowledged that pharmacoeconomic studies examining the cost-effectiveness of PD treated early in the course of the disease refer to “earliness” only in the sense of the disease being treated soon after standard PD diagnosis has been achieved. Standard approaches to PD diagnosis are, as previously noted, contingent upon the emergence of motor symptoms, and by that stage of the disease, significant neurological damage may already have occurred. If, however, early PD is defined as that period prior to the emergence of significant motor symptoms, before substantial neurological damage may have occurred, then few data are available that describe the real potential for cost savings.

It should also be noted that the largest part of direct costs in PD occur in advanced disease, when symptoms are at their most severe.26 It is, therefore, possible that therapeutic interventions offered to patients before significant deterioration has occurred—when the potential for preserving neurophysiologic structures is maximized—may offer long-term cost savings. Indeed, little evidence points to the likelihood of short-term savings with early therapeutic intervention (although little evidence in this area exists in general), but long-term cost savings are entirely credible based on the delay of levodopa therapy and of the motor symptoms that require more intensive therapeutic interventions.

Treatment Adherence and Maximizing Therapeutic Efficacy

Poor treatment adherence is a significant challenge to optimizing outcomes in PD, and any therapeutic strategy must take into consideration those factors impacting treatment adherence. Davis et al, employing insurance claims data from 30 managed care plans (using the Integrated Health Care Information Services Database), estimated that 61% of PD patients were nonadherent to therapy over a 12-month period.27 Davis et al further estimated that mean medical costs were significantly higher among nonadherent versus adherent subjects ($15,826 vs $9228; P <.01) despite the former having significantly lower prescription drug costs ($2684 vs $3854; P <.05). These data are consistent with results from a study published in 2011 showing that patients who were satisfactorily adherent (ie, >80% medication possession ratio [MPR]) to levodopa/carbidopa/entacapone therapy had 39% fewer PD-related hospitalizations, 9% greater PD-related prescriptions, 47% lower inpatient costs, and 18% lower total costs than patients with unsatisfactory adherence (ie, MPR <80%) (Figure 2).28 These results offer strong incentive for employing effective therapeutic interventions that are conducive to patient adherence.

Fargel et al surveyed 500 patients with PD and 592 neurologists who treated patients with PD, in order to determine the causes of poor adherence.29 The authors found that while physicians described themselves as being satisfied with the “pill load” of prescribed medications for their patients, the PD patients themselves were largely dissatisfied and wished for simpler drug regimens. In fact, a reduction in daily tablet intake was the most common request for treatment improvement in response to an open-ended question. Moreover, patient respondents expressed an interest in additional delivery systems, most of all transdermal patches, to facilitate the ease of delivery of their PD treatment, a view concurred with by neurologists.

These results are consistent with a recently published study comparing patient preference for pramipexole in oncedaily versus 3-times-daily formulations in patients with either early or advanced PD, which found an overwhelming preference (94.4%) for the once-daily formulation.30 In a recent study from Spain, in which 39 PD patients took part, the investigators observed: a) a strong correlation between treatment adherence to levodopa and the total number of daily drugs (as opposed to pills) prescribed, b) poorer adherence associated with higher levodopa doses, and c) higher rates of adherence in patients who were treated first with a dopamine agonist versus those first treated with levodopa.31 A transdermal patch of the dopamine agonist rotigotine, which has shown safety and efficacy in early PD—and non-inferiority to pramipexole—was recently approved for PD treatment by the FDA, and offers a therapy that is likely to be associated with higher rates of adherence compared with oral therapies.32-34

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