Parkinson s disease (PD) is a common and complex

n reports n Implications for Managed Care for Improving Outcomes in Parkinson s Disease: Balancing Aggressive Treatment With Appropriate Care Jack J. Chen, PharmD, FCCP, BCPS, CGP Abstract 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) For author information and disclosures, see end of text. 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 Managed Care & Healthcare Communications, LLC 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. 1 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, S322 n www.ajmc.com n october 2011

Balancing Aggressive Treatment With Appropriate Care 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 VOL. 17, No. 12 n The American Journal of Managed Care n S323

Reports 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. Once a correct diagnosis of PD is made, nonpharmacologic and pharmacologic interventions must be considered. Treatment guidelines and parameters are updated frequently to reflect new information and changes in treatment paradigms. 1 A general treatment approach for the treatment of early and advanced PD is illustrated in the Figure. 12 Accumulating evidence demonstrates that exercise in patients with PD results in improvement in function, gait, and QOL. 13 However, what constitutes the best type of exercise is still an open question. A physical therapist can assist in balance, gait, endurance, and strength training. Patients with PD should be encouraged to resume or continue physical exercise for as long as possible. Examples of exercise or mobility activities include bicycling, golfing, swimming, tennis, walking (conventional or treadmill), and even playing interactive, virtual reality, motion-controlled video games. A recent development is the use of rasagiline, a monoamine oxidase B (MAO-B) inhibitor, in patients with early PD who have minimal functional impairment. Large randomized, double-blinded, placebo-controlled studies, such as the TEMPO (TVP-1012 in Early Monotherapy for PD Outpatients) delayed start and the ADAGIO (Attenuation of Disease Progression with Azilect Given Once-Daily) delayed start studies, demonstrate that initiation of rasagiline in early stage PD slows the decline of motor function and is well tolerated. 14,15 The definition of functional impairment is highly patient specific. Factors such as comorbid conditions, cognitive status, employment, lifestyle, and patients desires must be considered when initiating pharmacotherapy. In a physiologically young patient experiencing minimal to mild functional impairment, monotherapy with amantadine, dopamine agonists, levodopa, or rasagiline can be considered. For mild to moderate impairment, a dopamine agonist is preferred, and for severe impairment, levodopa should be considered. For patients who are older or cognitively impaired, rasagiline (for mild impairment) or levodopa (for moderate to severe S324 n www.ajmc.com n october 2011

Balancing Aggressive Treatment With Appropriate Care n Figure. General Approach to the Management of Parkinson s Disease 12 Diagnosis of Parkinson s disease Nonpharmacologic therapy: Education, exercise, nutrition, psychosocial support Pharmacologic therapy for motor symptoms rasagiline Management of nonmotor symptoms a <65 years b anticholinergic or amantadine Need for additional symptomatic control Tremor >65 years b amantadine dopamine agonist or carbidopa/levodopa Bradykinesia, rigidity, tremor carbidopa/levodopa Management of motor fluctuations: Increase dosing frequency of levodopa Add MAO-B inhibitor or COMT inhibitor Add a dopamine agonist Management of peak-dose dyskinesia: Reduce dopaminergic drug dose Add amantadine Need for more symptomatic control of motor complications (despite optimized pharmacotherapy): surgery COMT indicates catechol-o-methyltransferase; MAO-B, monoamine oxidase B. a Nonmotor symptoms include anxiety, cognitive impairment, constipation, depression, dysphagia, orthostatic hypotension, sialorrhea, sleep disorders, speech impairment, and urinary incontinence. b Age is not the sole determinant of drug choice. Others factors such as cognitive function and overall safety and tolerability of drug should be considered, especially in the elderly. Adapted from Chen JJ, Nelson MV, Swope DM. Parkinson s disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey IM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw Hill; 2011:1033-1044. impairment) are preferred. Ultimately, all patients will require the use of levodopa, either as monotherapy or in combination with other agents. With chronic levodopa therapy, patients may begin to experience motor fluctuations, and the American Academy of Neurology assigns a high level of evidence for the addition of entacapone or rasagiline to extend the duration of activity of levodopa. 16 For management of levodopa-induced peak-dose dyskinesias, the addition of amantadine should be considered. Surgery is considered only in patients who need more symptomatic control or who are experiencing severe motor complications despite pharmacologically optimized therapy. In summary, individual treatment plans will evolve as the disease progresses, and must include consideration of short-term symptomatic relief as well as long-term effects. VOL. 17, No. 12 n The American Journal of Managed Care n S325

Reports Patient-specific factors that guide selection of therapies include the functional age of the patient, the patient s desired outcomes, cognitive status, the severity of motor features, and response to any previous PD therapies. Patient education should be communicated with realistic optimism. For example, it should be explained that although there is no cure for PD, modern medicine has many medications that can provide relief of symptoms. Nonpharmacologic interventions such as exercise should be encouraged, and nonmotor features of PD should not be neglected. Disease-Modifying Agents To date, several clinical trials have investigated the disease-modifying effects of various agents. The results of many studies have been disappointing. 17-19 However, the ADAGIO study 15 yielded promising results. The ADAGIO study is the largest study to specifically evaluate for disease modification in PD. The prospective, multicenter, placebo-controlled, double-blind clinical study had a delayed-start design developed to assess the efficacy of rasagiline as a disease-modifying compound in patients with early, non-disabling PD. The ADAGIO study was initiated based on results from a preliminary study which suggested that rasagiline given early in the disease might have disease-modifying benefits. 14 Patients in the ADAGIO study who received rasagiline 1 mg/day demonstrated a slower rate of disease progression compared with patients in the placebo group. Based on the efficacy and safety results of ADAGIO, there is some evidence to support the initiation of treatment with rasagiline in early PD. The outcomes associated with rasagiline should not be considered a class effect of MAO-B inhibitors; more trials are needed to help determine if there is a class effect. Specifically, the results of ADAGIO should not be extrapolated to selegiline, another commercially available MAO-B inhibitor. Selegiline is metabolized to the amphetamine derivatives L-methamphetamine and L-amphetamine, which are present in sufficient concentrations to produce toxic effects in experimental models and side effects in patients with PD. 20 Additionally, recent data suggest that chronic amphetamine use is associated with an increased lifetime risk of PD. 21 Conclusion Parkinson s disease is associated with significant direct and indirect medical costs and impaired QOL. Differences in managed care and insurance plans affect clinical care, which in turn affects patient outcomes and QOL. Periodic attention to new data on short- and long-term clinical efficacy and safety, disease modification, and nonmotor symptoms associated with PD will allow clinicians and payers to optimize management and care plans for patients with PD. Author Affiliations: Department of Pharmacotherapy and Outcomes Science, Department of Neurology, School of Medicine, Loma Linda University, Loma Linda, CA. Funding Source: This activity is supported by an educational grant from Teva Neuroscience, Inc. Author Disclosure: Dr Chen reports serving as an advisory board member/consultant for and receiving honoraria from Chelsea Pharmaceuticals and Teva Neuroscience, Inc. He has served on the speaker s bureau for Teva Neuroscience, Inc. Authorship Information: Concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content. Address correspondence to: E-mail: jjchen@llu.edu. REFERENCES 1. Olanow CW, Stern MB, Sethi K. The scientific and clinical basis for the treatment of Parkinson disease. Neurology. 2009;72(21 suppl 4):S1-S136. 2. Dorsey ER, Constantinescu R, Thompson JP, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 2007;68:384-386. 3. Chen JJ. 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