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

Implications for Managed Care for Improving Outcomes in Parkinson's Disease: Balancing Aggressive Treatment With Appropriate Care

Jack J. Chen, PharmD, FCCP, BCPS, CGP

Disability in Parkinson’s disease (PD) is due not only to progressive impairment in balance, gait, and motor-related tasks, but also to several nonmotor symptoms affecting autonomic, neuropsychiatric, and sensory functions. The prevalence of PD in the United States is rising due to the expanding elderly population. Direct medical costs associated with PD are significant and influenced by level of disability and associated complexity of management. As new treatments are made available, reevaluation of treatment benefits and paradigms is warranted, for both motor and nonmotor symptoms of PD, to better manage outcomes. In addition to evaluation of symptomatic therapies for PD, attention to advances in disease-modifying therapies and to management of nonmotor symptoms should be an integral component of PD surveillance in the managed care environment.

Am J Manag Care. 2011;17:S322-S327

Parkinson’s disease (PD) is a common and complex movement disorder characterized by progressive neurodegeneration, loss of nigrostriatal dopaminergic and extranigral neurons, and functional disability due to motor and nonmotor symptoms.1

Variability in PD phenotype and progression is well recognized and serves as the basis for individualizing patient therapy. Over the lifetime course of PD, shifts in individual therapeutic response, emergence of drug-related adverse effects and motor complications, development of levodopa-unresponsive symptoms, and the onset of additional PD-related nonmotor symptoms add to the complexity of patient management, and constant, ongoing modification of pharmacotherapy should be expected. Disability in PD is due not only to progressive impairment in balance, gait, and movement-related tasks, but also to several nonmotor symptoms affecting autonomic, neuropsychiatric, and sensory functions.The goal of therapy for PD is to improve outcomes in domains of motor and nonmotor symptoms, activities of daily living, and quality of life (QOL), while minimizing acute and long-term side effects. The prevalence of PD in the United States is rising due to the expanding elderly population and the number of individuals with PD is expected to double in the next 20 years.2 Such an increase will likely place a significant burden on care systems and caregivers given the associated disability and amount of caregiving required for this patient population. Additionally, it can be anticipated that PD will continue to be associated with significant direct and indirect economic costs due to symptom management and disability.

Direct medical costs associated with PD are significant and influenced by level of disability and associated complexity of management.3 As new treatments are made available, reevaluation of treatment benefits and paradigms is warranted, for both motor and nonmotor symptoms of PD, to better manage outcomes.

Economic and Quality of Life Issues in PD

The introduction of levodopa in 1967 was a significant advance in PD therapy and improved QOL for treated patients with PD. However, despite therapy, patients with PD continue to experience deterioration in QOL with disease progression. Additionally, even levodopa-treated patients develop considerable disability after 5 to 10 years of disease despite expert treatment with available medications.3 In particular, the development of gait/balance disturbances and dementia (all of which are generally unresponsive to dopaminergic therapy) significantly increases the mortality risk due to complications (eg, immobility, falls, and nursing home placement).3

The annual economic impact of PD in the United States is estimated at $10.8 billion, 58% of which is related to direct medical costs.4 Annual direct medical costs per patient with PD are estimated at between $10,043 and $12,491 while annual indirect costs are estimated at $25,326 per patient. Nursing home care is the largest component of direct medical costs at approximately 40%, while prescription drugs account for 20% or less. Although more difficult to measure, annual indirect costs for both patients and caregivers, including lost wages due to termination or early retirement and switching to individual health insurance, can be very significant.

In 1 study, Medicare Part D beneficiaries with PD were found to repeatedly reach the drug benefit threshold due to greater utilization of brand-name medications for which there were limited available generic alternatives.5 Levodopa, which is one of the most effective medications for PD, is available generically; however, clinicians and payers should keep in mind that long-term treatment is unfortunately associated with the development of motor complications (eg, dyskinesias and fluctuations), which may necessitate the use of adjunctive medical and surgical therapies, all of which ultimately increase direct and indirect economic costs. When evaluating drug economics, thoughtful consideration should be given to not only the issue of generic and brand-name availability and cost, but also to short- and long-term effects.

Payer and provider plans do make a difference in patient satisfaction and QOL. In a recently published European study, QOL was reported to be better in patients with PD who had private insurance compared with patients with PD who had government-provided insurance.6 Just as statistically significant differences are important to consider when evaluating the validity of research data, clinically significant differences are important for determining therapeutic value. Likewise, just as economically significant differences in drug cost are important to consider when evaluating formulary placement, QOL significance must also be considered. Even though drugs comprise a smaller proportion of direct costs, the associated QOL benefits due to delayed disability (motor and nonmotor) and maintenance of employability and independence can be significant and must be considered. QOL considerations extend and portray the impact of therapy beyond what can be described by statistical and economic parameters.

Not only motor symptoms but also nonmotor symptoms (eg, dementia, depression, orthostatic hypotension, sleep disorders, urinary dysfunction) have a significant negative effect on health-related QOL; oftentimes more so than motor symptoms.7 In 1 study, utilizing a large Veterans’ Administration cohort, patients with PD exhibited lower scores on the physical and mental health dimensions of health-related QOL compared with patients with 8 other neurological or chronic conditions, including angina/coronary heart disease, congestive heart failure, diabetes, and stroke.8

Clinical Course and Diagnostic Issues in PD

The clinical course of PD is postulated to be characterized by a prodromal phase characterized by nonmotor symptoms such as constipation, hyposmia (smell impairment), and rapid eye movement sleep behavior disorder.1 Such symptoms may occur up to 10 years prior to motor symptoms and diagnosis. Given increased knowledge of the premotor phenotype of PD, a battery of tests including assessment of nonmotor features, olfactory testing, and neuroimaging may one day provide a means of reliably diagnosing PD at an early stage of the disease.

Currently, clinical diagnosis is based on the presence of obvious motor features consisting of bradykinesia (slowness of movement), tremor, and/or rigidity.1 As PD progresses, patients exhibit disability due to bradykinesia, rigidity, gait and balance difficulty, and falls. In particular, the onset of balance impairment, falling, or cognitive impairment is a hallmark of disability. Side effects (eg, daytime sleepiness, orthostatic hypotension, psychosis) and long-term effects due to pharmacotherapy (eg, levodopa-related dyskinesias, motor fluctuations, neuropsychiatric complications, dopamine-agonist induced hallucinations) also often complicate therapy.

For clinically indeterminate cases, some clinicians will provide an acute levodopa challenge or a brief trial of levodopa as a means of diagnosis. However, in the United States, this method is not routinely recommended.9 Acute exposure to a therapeutic dose of levodopa can expose the patient to an unnecessary risk of adverse effects. Additionally, if the patient experiences a positive clinical response to levodopa, the patient and clinician are in essence committed to levodopa as the main form of therapy, and the patient is not likely to accept non-levodopa agents as monotherapy. For clinically indeterminate cases, referral to a movement disorders specialist or use of neuroimaging can be recommended.

Recently, a radioligand to measure presynaptic dopamine transporters with single photon emission computed tomography (SPECT) has become commercially available in the United States. The DaTscan is a striatal SPECT imaging method utilizing ioflupane iodine-123 as a diagnostic aid and has demonstrated good sensitivity and specificity for detecting striatal dopamine deficiency.10 However, the imaging results do not differentiate between the various dopamine deficiency disorders (such as idiopathic PD from atypical parkinsonism or dementia with Lewy bodies) and should be considered as an adjunct to findings from the clinical assessment and history. However, in clinically indeterminate cases, the imaging method can differentiate between intrinsic parkinsonism and other disorders such as drug-induced parkinsonism, dystonic tremor, essential tremor, normal pressure hydrocephalus, psychogenic parkinsonism, Wilson’s disease, and various gait disorders of the elderly, all of which may mimic PD but are not associated with dopamine deficiency.

Although disease progression is patient-specific and highly variable, ultimately all patients with PD will require symptomatic therapy, and eventually, all patients will end up on a levodopa-based regimen. It is generally accepted that younger patients treated with levodopa are at greater risk of developing motor fluctuations and dyskinesias as compared with older patients; therefore, if symptoms are mild to moderate, the use of non-levodopa regimens is preferable in younger patients.11

Even with optimal drug therapy, many patients will develop balance and gait impairment as the disease progresses, and simple activities such as ambulating around the house to accomplish activities of daily living as well as traveling in the community for leisure, recreational, and social activities will become prohibitively difficult. The onset of such disability also has a significant impact on caregivers, because at this point caregivers become increasingly involved.

Management of PD

The goal of the management of PD is to improve motor and nonmotor symptoms so that patients are able to obtain the best function for their stage of disease. For most community- dwelling patients, this means preserving the ability to perform instrumental activities of daily living, independent living, and QOL in all domains (eg, physical, psychological, social). With the progression of motor and nonmotor symptom severity, the onset of disability, and greater dependence on caregiver assistance, the emphasis will shift to preserving basic activities of daily living and specific QOL domains that are important to the patient. Ultimately, with advanced PD, therapeutic goals will shift to a focus on providing palliative therapy. At various stages of the disease, non-pharmacologic interventions (eg, occupational, physical, and speech therapy) also play a vital role.

Specific objectives to consider when selecting an intervention include preservation of the ability to perform activities of daily living; improvement of mobility, gait, and balance; minimization of adverse effects; treatment complications; putative disease modification; and management of nonmotor features such as cognitive impairment, depression, fatigue, orthostasis, and daytime and nighttime sleep disorders. To accomplish some of these objectives, consultation with a specialist (eg, in movement disorders, physical therapy, psychiatry, sleep medicine) is helpful.

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