Part 2: Treatment of Motor Symptoms

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Supplements and Featured Publications, Parkinson’s Disease: Quality Assessment and Improvement of Care, Volume 14, Issue 2 Suppl

In the absence of a cure, the primary goals in managing Parkinson’s disease (PD) are to preserve functionality and health-related quality of life. Meeting these goals can minimize healthcare-resource utilization and long-term healthcare costs. Although effective treatment of motor symptoms of the disease is a central consideration to facilitate improved outcomes, management of nonmotor symptoms is now recognized as an equally important target of intervention, since nonmotor symptoms can contribute greatly to disability. The article addresses the current treatment options of choice for reducing motor symptoms of PD and their most rational use. Cost-effectiveness is a major consideration for managed care and is also analyzed for many available treatment options.

(Am J Manag Care. 2008;14:S49-S58)

Parkinson’s disease (PD) is a chronic neurodegenerative condition associated with a significant burden on patients, their caregivers, and society. Direct and indirect costs related to PD are estimated to exceed $20 billion annually already, a figure projected to double in the future because of the rising number of affected individuals. Part 11 discussed the burden of PD, as well as its etiology, pathophysiology, diagnostic considerations, and methods of patient assessment, with implications for managed care. Part 2 discusses the therapeutic options available to treat motor symptoms of PD, costs of these options, and their cost-effectiveness in relation to improving outcomes. Nonmotor neuropsychiatric comorbidities will be addressed in Part 3.2

Table 1

Table 2

Pharmacologic Therapy of Motor Symptoms presents the most commonly used agents to treat motor symptoms in PD and their cost for 1 month of therapy. Primary adverse effects of these drugs are listed in .

Goals of Therapy. There currently is no cure for PD, and no existing therapy has been shown clearly to slow or reverse progression of the disease.3 The most important goals of management are thus to preserve functional independence and health-related quality of life (HRQOL).4-6 Achievement of these goals can reduce the need for healthcare resource utilization and reduce total costs. Toward this end, treatment is directed at providing symptomatic relief, for both motor and nonmotor symptoms, while minimizing undue adverse effects.4

However, this has proven problematic in practice. The most effective therapy for treating motor symptoms, levodopa, has been associated with an increased risk of motor fluctuations. This risk is greatest in younger-onset patients, with escalating dosages of medication and longer duration of treatment. These motor fluctuations can impair HRQOL and cause significant functional and social disability,3,4,7 directly contrary to management goals. Levodopa-induced motor fluctuations and dyskinesias are difficult to treat.7 This has led to a treatment paradigm in PD of maximizing therapy with other agents— levodopa-sparing therapies—for as long as possible before using levodopa.4,6 However, this paradigm is not adhered to by all clinicians.

When to Start Therapy. Timing the onset of therapy remains controversial. Prior to initiating symptomatic therapy for the mildly afflicted patient who is not functionally impaired, enrolling the patient in a neuroprotection trial should be considered. Some clinicians and specialists initiate treatment for very mild symptoms in view of studies that suggest early treatment may offer an advantage.8-10 If early therapy is considered, patient age should be a factor in regard to treatment selection. Younger patients with early PD (young-onset) are more prone to motor fluctuations with chronic levodopa treatment. In these patients, dopamine agonists are considered the first line by many clinicians (discussed below).

Although there was concern that levodopa itself enhanced progression of PD, current clinical evidence does not support this idea. There is no evidence that shows worsening of PD with levodopa. To the contrary, recent studies suggest that levodopa may actually slow progression of disease symptoms.8-11 Thus, early therapy with levodopa should not be withheld based on this concern.

In contrast to very early treatment of symptoms, other clinicians prefer to delay dopaminergic therapy for PD until clinically significant disability or impairment occurs. In these mildly affected patients, nondopaminergic therapy, such as amantadine or monoamine oxidase type B (MAO-B) inhibitors, is an option. The reluctance to start dopaminergic therapy early in the disease reflects concerns about the adverse effects of these agents and the long-term consequences of treatment. Side effects, including sedation, nausea, and orthostatic hypotension, may be more disabling than the motor impairment.

Whether an early or later treatment approach is adopted, maintaining functionality for as long as possible is the goal of clinical management. This not only improves HRQOL of the patient but also reduces direct costs associated with the need for office visits and lessens indirect costs by mitigating dependence on caregivers and allowing less time off from work.

Levodopa: Cornerstone of Therapy. Levodopa remains the most effective agent for treatment of motor symptoms in PD.3-6,8,10,12 As a prodrug of dopamine, levodopa crosses the blood-brain barrier (BBB) and is decarboxylated to dopamine in the nigrostriatal pathways.6 Levodopa is always given with carbidopa, a peripheral dopa-decarboxylase inhibitor, which prevents peripheral metabolism of levodopa and allows a higher percentage of a dose to cross the BBB. Combined use with carbidopa also minimizes the adverse effects of peripheral dopamine, such as nausea and hypotension.5

Initially, patients will have a good and sustained response to levodopa with small amounts of levodopa given 3 times a day. This “honeymoon” period may last for up to 5 years.8,11 However, as treatment continues and PD progresses, motor complications occur in virtually all patients. These motor complications include a shortened duration of drug benefit termed “wearing off” and drug-induced dyskinesias. The half-life of levodopa is approximately 90 minutes. With progressive disease, the benefits of each dose become shorter, with a wearing off of benefit before the next dose. Additionally, patients may experience loss of benefit from a usually effective dose, or unpredictable “on-off” in which there is a sudden loss of drug effect and recurrence of severe PD symptoms termed on-off motor fluctuations.3,4,8,11 The motor complications occur in up to 70% of patients after 9 years of treatment.13

With disease progression, the nonmotor features of PD, including depression, anxiety, autonomic dysfunction, cognitive impairment, and sleep disturbance, become increasingly important. These nonmotor features often do not respond to dopaminergic therapy and must be identified and treated.3 Postural instability is a motor symptom that may become resistant to therapy, resulting in falls and injury despite good overall control of motor symptoms.4,11 HRQOL declines further as these symptoms worsen. Anxiety, depression, and/or panic attacks can be seen during off periods, and can be very distressing to the patient.

Optimizing Levodopa Therapy. Optimizing treatment in PD is of extreme importance to care management, because this assures the best possible chance to minimize long-term disability. The currently available drugs provide an array of choices for optimizing benefit. Furthermore, patient education, encouragement of physical activity and exercise, and monitoring drug compliance play a major role in maximizing function and achieving treatment goals.

Levodopa treatment is an important part of longterm treatment. Applying methods to maximize the duration of effect of levodopa and minimize the side effects is paramount. For example, nausea and vomiting are prominent adverse effects during the initiation of levodopa therapy. This side effect may reduce the compliance of the PD patient. By adding additional carbidopa, this side effect can be greatly minimized.4,5,8 Some patients may require higher doses of carbidopa, up to 200 mg/day, to adequately control nausea; this is possible by adding carbidopa alone to the levodopa/carbidopa regimen.8,11

Controlled-release levodopa/carbidopa formulations may be considered in patients with wearing-off effects. However, erratic absorption of this dosage form may be seen in some patients. The unpredictability of controlled-release formulations may result in a slower and unpredictable onset of action and at times worsening dyskinesias in the afternoon or evening. Switching from standard levodopa/carbidopa to the controlled-release formulation may also be somewhat troublesome, requiring dose titration.11 Initiating therapy with the controlledrelease formulation may be advantageous, although studies have not been convincing.11,14 In patients with gastric slowing and/or advanced motor fluctuations, the use of liquid levodopa/carbidopa may allow more precise titration over the course of the day, but is cumbersome because of the need to drink appropriate amounts every hour. Liquid levodopa or the orally dissolving formulation of levodopa may also be useful in patients who are unable to swallow and may be useful during off periods.11

Table 3

Suggestions for managing dyskinesias and motor fluctuations during levodopa therapy are shown in .7,8,11,12

Dopamine Agonists. Dopamine agonists have been used as monotherapy in early PD or in combination with levodopa in more advanced disease. Adverse effects of dopamine agonists are more common than with levodopa, and slow dose titration over time is indicated. There is increasing use of these agents as initial therapy in PD, to help delay the need for levodopa and reduce overall levodopa dosage. Controlled comparisons of dopamine agonists, including ropinirole and pramipexole with levodopa as initial therapy, have demonstrated a reduction in the wearing-off phenomenon and dyskinesias in the dopamine agonist–treated groups. These reductions were seen even when levodopa was added to the dopamine agonist group to control parkinsonian symptoms.5,11,13,15-17 In these trials, subjects treated with dopamine agonists did not have as much improvement in their motor scores as the levodopa group; however, patients in both groups reported good subjective control of symptoms. Some patients have achieved good motor control with dopamine agonist monotherapy for up to 5 years.

However, because of the less robust effect of dopamine agonists, virtually all patients will eventually require the use of levodopa.

Many specialists start therapy with dopamine agonists in younger patients with PD (<50 years of age), because these patients are much more prone to developing severe motor complications.10,18,19 In contrast, levodopa/carbidopa monotherapy is advocated by most specialists over dopamine agonists for initial therapy in older patients and those with cognitive dysfunction. Dopamine agonists are more likely than levodopa to cause cognitive side effects including confusion and hallucinations, particularly in the elderly.8,10,18,19

When given as adjunctive therapy to levodopa in more advanced disease, dopamine agonists have improved Unified Parkinson&#8217;s Disease Rating Scale (UPDRS) scores, increased on time during wakeful hours, and enabled lower doses of levodopa to be given.

Rotigotine is a unique dopamine agonist with a transdermal patch delivery system. It may offer more stable plasma levels, is given only once daily, and is effective in both early and advanced disease.11,20 This agent may help to optimize compliance with therapy. However, only the lower-dose patches are currently available in the United States, limiting its usefulness to early treatment.

Apomorphine is a dopamine agonist given subcutaneously for more advanced disease and resistant motor fluctuations. Apomorphine has a rapid onset of action and a duration of benefit of approximately 90 minutes. It can be a very effective treatment for patients with unpredictable off times, dosage failures, and early-morning off times. Apomorphine is a potent emetic, and trimethobenzamide should be given before initiating therapy.11

Rotigotine, apomorphine, pramipexole, and ropinirole are nonergot dopamine agonists. They have not been associated with vasoconstriction-related events, valvular heart abnormalities, or retroperitoneal fibrosis, which have been associated with ergot dopamine agonists.12 There appears to be no significant difference in clinical efficacy between the offset to varying degrees by an increased risk of dyskinesias, which may require a decrease in total levodopa dose.4,25

Amantadine. Amantadine is an older medication with many different actions in the central nervous system, including inhibition of N-methyl-D-aspartate receptors, enhancement of dopamine release from presynaptic terminals, and modest anticholinergic activity.18 Amantadine has demonstrated effectiveness for relieving tremor in early PD. In more advanced illness, amantadine has been shown to improve levodopa-induced dyskinesias.4,5,18 Amantadine requires dose reduction in renal impairment and should be used with caution in patients with cognitive impairment. The primary role of amantadine is in reduction of dyskinesia.7

Anticholinergic Agents. Anticholinergic agents, such as trihexyphenidyl and benztropine, are the oldest treatments that have been used in PD. They are most effective for treating resting tremor. Anticholinergics are typically reserved for the younger patient (<60 years of age) with predominant tremor illness and preserved cognitive function. These agents should be used with caution in older patients because of their potential for side effects, including constipation, blurry vision, urinary retention, confusion, and hallucinations.4,5,8 One benefit of both trihexyphenidyl and benztropine is their low cost.26

Guidelines for Treating Motor Symptoms in PD. The following comments and recommendations are based on guidelines, recommendations in the literature, and opinions of experts in the field:

&#8226; Levodopa should generally be considered for initial therapy in older patients with more advanced disease.10,18

&#8226; Although its use can be delayed, levodopa will eventually be required in virtually all patients as the disease progresses.

&#8226; In patients with a combination of motor wearing off and peak-dose dyskinesias, levodopa dose reduction and use of adjunctive therapies may be useful. In patients with medically resistant motor fluctuations, deep brain stimulation (DBS) surgery should be considered.8

Surgery for PD. DBS of the subthalamic nucleus (STN) is an effective surgical procedure in appropriate candidates for treating medically resistant motor symptoms of PD and improving HRQOL.27,28 This technique is now considered the surgical method of choice for patients with advanced disease.11,29 DBS-STN has been shown to significantly reduce both the primary symptoms of PD and its motor complications, including tremor, bradykinesia, wearing off, dyskinesias, and dystonia. Many patients treated with DBS-STN may reduce their medication burden. A recent meta-analysis showed a 55.9% reduction in daily levodopa equivalent dosage.30 This meta-analysis also showed a 69.1% reduction in dyskinesias, a 68.25% reduction in off periods, and a 34.5% improvement in quality of life. Optimal patients have medically refractory motor fluctuations or tremor, stable medical problems, and normal cognitive function.8,27,28 Outcomes of surgery are better in younger patients.8,27 Side effects of surgery include hemorrhage, stroke, infection or failure of hardware, and memory loss.

Pallidotomy or thermocoagulation of the globus pallidus interna can also alleviate major symptoms of PD, but is now used less often than DBS. DBS is more effective than pallidotomy for improving primary motor symptoms.11

Treatment Effects on HRQOL in PD HRQOL is poor in patients with PD, particularly in advanced disease, typically related to growing disability.29,31-33 Nonmotor symptoms, especially depression and cognitive impairment, and motor complications of levodopa contribute greatly to a poor HRQOL.25,34,35 Declining HRQOL is associated with increases in both direct and indirect costs,30 emphasizing the importance of effective treatment strategies to reduce disability, optimize levodopa therapy, and prevent or treat nonmotor symptoms.

The impact of drug therapy or other strategies to improve HRQOL has not been well studied, in part related to lack of a standardized HRQOL assessment instrument. However, in studies that are available (using various measurements for HRQOL), the following have been shown to improve HRQOL to some degree in patients with PD: DBS-STN29,36; unilateral pallidotomy36; rasagiline in early PD22,36; entacapone adjunct to levodopa (conflicting data)36; oral levodopa33; duodenal infusion of levodopa versus oral levodopa36; switching from standard levodopa to controlled-release levodopa36; pramipexole 33,37; and patient education regarding aspects of PD.29

In a 4-year study, HRQOL improvement was seen with levodopa and pramipexole, each given as monotherapy, in patients with early PD.33 Improvement was mainly seen during the first year, then declined during the next 3 years of follow-up. HRQOL benefits over the 4-year period tended to be greater with pramipexole. Benefits with pramipexole appeared to be mediated by improvement of nonmotor features, in contrast to improved motor function with levodopa.

Nonpharmacologic Therapy

Ropinirole, pramipexole, selegiline, and rasagiline are being investigated for putative neuroprotectant (disease-modifying) properties,3-5,8,12,22,23 which implies the ability to spare or salvage dopaminergic cells from the progressive neurodegenerative processes in PD and slow disease progression.8 However, based on a recent evidence-based review by the American Academy of Neurology38 and a review by Jankovic,12 no therapeutic agent has unequivocally demonstrated neuroprotection in PD.

Managed Care Considerations

&#8226; Bromocriptine was better than levodopa29

&#8226; Levodopa/carbidopa controlled-release was better than standard levodopa/carbidopa29&#8226; Levodopa/carbidopa/entacapone was better than standard care42

&#8226; Rasagiline as levodopa adjunct was better than standard care40

Costs of care for PD are rising. Greater recognition of PD in the community, use of the most effective modalities for its treatment, and optimization of this treatment can lead to improved functionality and HRQOL of the patient, which will likely reduce costs over time. Choice of initial symptomatic therapy is an important determination of long-term function. This can be achieved with proper use of levodopa/carbidopa, dopamine agonists, MAO-B inhibitors, and COMT inhibitors, as well as effective treatment of nonmotor symptoms. In particular, delaying the need for levodopa therapy in early disease with dopamine agonists and controlling levodopa-related motor complications in more advanced disease with COMT inhibitors, MAO-B inhibitors, and dopamine agonists can have a major positive impact on patient disability and long-term healthcare costs.

2. Weintraub D, Comella CL, Horn S. Parkinson’s disease— Part 3: neuropsychiatric symptoms. Am J Manag Care. 2008;14:S59-S69.

4. Rezak M. Current pharmacotherapeutic treatment options in Parkinson’s disease. Dis Mon. 2007;53:214-222.

6. Pallone JA. Introduction to Parkinson’s disease. Dis Mon. 2007;53:195-199.

8. Simuni T. Diagnosis and management of Parkinson’s disease. Medscape Neurology, August 30, 2007. Accessed December 14, 2007.

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16. Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE; 056 Study Group. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. N Engl J Med. 2000;342:1484-1491.

18. Lees A. Alternatives to levodopa in the initial treatment of early Parkinson’s disease. Drugs Aging. 2005;22:731-740.

20. Naidu Y, Chaudhuri KR. Transdermal rotigotine: a new non-ergot dopamine agonist for the treatment of Parkinson’s disease. Expert Opin Drug Deliv. 2007;4:111-118.

22. Fernandez HH, Chen JJ. Monoamine oxidase inhibitors: current and emerging agents for Parkinson disease. Clin Neuropharmacol. 2007;30:150-168.

24. deMarcaida JA, Schwid SR, White WB, et al. Effects of tyramine administration in Parkinson’s disease patients treated with selective MAO-B inhibitor rasagiline. Mov

25. Tetrud JW. Balancing short-term symptom control and long-term functional outcomes in patients with Parkinson’s disease. CNS Spectr. 2007;12:275-286.

27. Okun MS, Fernandez HH, Rodriguez RL, Foote KD. Identifying candidates for deep brain stimulation in Parkinson’s disease: the role of the primary care physician.

28. Cozzens JW. Surgery for Parkinson’s disease. Dis Mon. 2007;53:227-242.

30. Kleiner-Fisman G, Herzog J, Fisman DN, et al. Subthalamic nucleus deep brain stimulation: summary and meta-analysis of outcomes. Mov Disord. 2006;21(supp 14):S290-S304.

32. Gage H, Hendricks A, Zhang S, Kazis L. The relative health related quality of life of veterans with Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2003;74:163-169.

34. Pechevis M, Clarke CE,Vieregge P, et al. Effects of dyskinesias in Parkinson’s disease on quality of life and health-related costs: a prospective European study. Eur J Neurol. 2005;12:956-963.

36. Martinez-Martin P, Deuschl G. Effect of medical and surgical interventions on health-related quality of life in Parkinson’s disease. Mov Disord. 2007;22:757-765.

38. Suchowersky O, Gronseth G, Perlmutter J, et al. Practice parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66:976-982.

40. Hudry J, Rinne JO, Keranen T, Eckert L, Cochran JM. Cost-utility model of rasagiline in the treatment of advanced Parkinson’s disease in Finland. Ann Pharmacother. 2006;40:651-657.

42. Findley LJ, Lees A, Apajasalo M, Pitkänen A,Turunen H. Cost-effectiveness of levodopa/carbidopa/entacapone (Stalevo) compared to standard care in UK Parkinson’s disease patients with wearing-off. Curr Med Res Opin. 2005;21:1005-1014.

44. Eskandar EN, Flaherty A, Cosgrove GR, Shinobu LA, Barker FG 2nd. Surgery for Parkinson disease in the United States, 1996 to 2000: practice patterns, shortterm outcomes, and hospital charges in a nationwide sample. J Neurosurg. 2003;99:863-871.