helplinedonate
  • Announcements

    • ForumAdmin

      Frequently Asked Questions - Step by step guides

      Do you need assistance registering, logging in, posting, etc? Please visit the all new Frequently Asked Question Forum for step-by-step guides. Click the link below to access these helpful guides. Frequently Asked Questions
    • ForumAdmin

      Recursos Nuevos en Español

      http://www.parkinson.org/ayuda   http://www.parkinson.org/espanol    
    • ForumAdmin

      Línea de Ayuda 1-800-473-4636

      Línea de Ayuda 1-800-473-4636   ¿Qué es la línea de ayuda 1-800-4PD-INFO (473-4636) de la Fundación Nacional de Parkinson? Es un número de teléfono gratuito que ayuda a las personas con la enfermedad de Parkinson, sus familiares, amigos y profesionales de salud, a solucionar diferentes inquietudes.   La línea de ayuda ofrece: Información actualizada Apoyo emocional Referidos a profesionales de salud Recursos comunitarios Amplia variedad de publicaciones gratis    
kholden

Treatment of Early Parkinson's Disease

3 posts in this topic

WK_LWW_article_level.png
Treatment of Early Parkinson's Disease

Rajesh Pahwa, Kelly E. Lyons

Curr Opin Neurol. 2014;27(4):442-449. 

Abstract and Introduction Abstract

Purpose of Review. This review summarizes currently available treatment options and treatment strategies, investigational treatments, and the importance of exercise for early Parkinson's disease.

Recent Findings. The available treatment options for early Parkinson's disease have changed little in the past decade and include carbidopa/levodopa, dopamine agonists, and monoamine oxidase type B (MAO-B) inhibitors. However, we discuss changes in treatment strategies, including dosing and the use of combination therapy used in an attempt to reduce or delay the appearance of motor complications and other adverse events. We will also review several investigational treatments that have shown promise for the treatment of early Parkinson's disease, including a new extended release formulation of carbidopa/levodopa (IPX066), safinamide which inhibits MAO-B, dopamine uptake and glutamate and pardoprunox which is a 5HT-1A agonist and a partial dopamine agonist. Finally, we discuss recent studies focusing on exercise as an important component in the management of early Parkinson's disease.

Summary. Advances in the management of early Parkinson's disease include evolving treatment strategies, new investigational treatments, and earlier implementation of various forms of exercise.

Introduction

Parkinson's disease affects an estimated one million persons in the United States, with over five million affected worldwide, and these estimates are expected to increase substantially in the next few decades.[1] Despite the increasing prevalence, the approved agents for the early management of Parkinson's disease have changed little in the past decade; however, there have been advances in drug delivery, dosing, and the use of combination therapy in an attempt to reduce adverse events. The available treatments continue to focus on the dopaminergic system and include primarily carbidopa/levodopa, monoamine oxidase type B (MAO-B) inhibitors, and dopamine agonists.[2] Current research on the early management of Parkinson's disease focuses on improved and more consistent drug delivery systems, targeting alternate neurotransmitter systems and the identification of neuroprotective therapies for Parkinson's disease. There has also been an increased interest in earlier intervention with various forms of exercise in addition to pharmacological treatments.[3] This article includes a review of the available treatment options for early Parkinson's disease, published trials of new pharmacological treatments under investigation for the symptomatic treatment of early Parkinson's disease, and the potential benefits of exercise in early Parkinson's disease.

Currently Available Treatment Options for Early Parkinson's Disease

The selection of the appropriate treatment regimen for early Parkinson's disease is highly individualized. Many factors should be considered, including the patient's age, symptoms, symptom severity, occupational status, lifestyle, cognitive, behavioral and psychiatric status, and other medical comorbidities. Current treatment options for early Parkinson's disease include carbidopa/levodopa, dopamine agonists (immediate and extended release formulations of pramipexole and ropinirole, and transdermal rotigotine), and MAO-B inhibitors (rasagiline and selegiline), which are discussed in more detail below ( ).[4–18] Amantadine, an N-methyl-D-aspartate (NMDA) glutamate antagonist, is less commonly used, but has been shown in small studies to provide mild improvements in the cardinal symptoms of Parkinson's disease.[19] Anticholinergics may be used in younger patients to control tremor, but their use is limited because of the risk of cognitive impairment, confusion, hallucinations, dry mouth, and constipation.[20]

Table 1.  Double-blind, randomized studies of available treatment options for the early management of Parkinson's disease Study Treatment Dosage Study Duration Efficacy (placebo-adjusted change) ELLDOPA [4] carbidopa/levodopa 150 mg/day 24 weeks 3.0 pts UPDRS motor     300 mg/day   5.9 pts UPDRS motor     600 mg/day   7.1 pts UPDRS motor FIRST STEP [5] carbidopa/levodopa/entacapone 25/100/200 t.i.d. 39 weeks 7.0 pts UPDRS motora   carbidopa/levodopa 25/100 t.i.d.   6.2 pts UPDRS motora STRIDE PD [6] carbidopa/levodopa/entacapone 25/100/200 four times daily (q.i.d.) 134 weeks 8.4 pts UPDRS Motor+ADLa   carbidopa/levodopa 25/100 q.i.d.   7.2 pts UPDRS motor+ADLa PSG [7] pramipexole 1.5 mg/day 10 weeks 5.2 pts UPDRS Total     3.0 mg/day   5.1 pts UPDRS Total     4.5 mg/day   5.9 pts UPDRS Total     6.0 mg/day   5.2 pts UPDRS Total Shannon et al. [8] pramipexole 3.8 mg/day (mean) 24 weeks 6.0 pts UPDRS motor PramiBID [9] pramipexole 0.5 twice daily (b.i.d.) 12 weeks 3.2 pts UPDRS motor     0.75 b.i.d.   3.4 pts UPDRS motor     0.5 t.i.d.   3.3 pts UPDRS motor Hauser et al. [10] pramipexole immediate release 3.03 mg/day (mean) 18 weeks 3.2 pts UPDRS motor   pramipexole extended release 3.05 mg/day (mean)   3.2 pts UPDRS motor Adler et al. [11] ropinirole 15.7 mg/day (mean) 6 months 4.7 pts UPDRS motor PSG [12] rotigotine transdermal patch 4.5 mg/day 11weeks 0.9 pts UPDRS motor     9.0 mg/day   1.9 pts UPDRS motor     13.5 mg/day   3.9 pts UPDRS motor     18.0 mg/day   3.8 pts UPDRS motor Watts et al. [13] rotigotine transdermal patch 5.7 mg/day (mean) 6 months 4.8 pts UPDRS motor DATATOP [14] selegiline 10 mg/day 3 months 1.9 pts UPDRS motor Allain et al. [15] selegiline 10 mg/day 3 months 1.0 pts UPDRS motor Palhagen et al. [16] selegiline 10 mg/day 6 months 4.0 pts UPDRS motor TEMPO [17] rasagiline 1.0 mg/day 26 weeks 2.7 pts UPDRS motor     2.0 mg/day   1.7 pts UPDRS motor ADAGIO [18] rasagiline 1.0 mg/day 36 weeks 3.0 pts UPDRS Total     2.0 mg/day   3.2 pts UPDRS Total

ADL, activities of daily living; UPDRS, Unified Parkinson's Disease Rating Scale.

aStudy not placebo controlled.

Carbidopa/Levodopa

Carbidopa/levodopa continues to be the most effective treatment for all stages of Parkinson's disease. It is well established that the long-term use of high doses of levodopa generally leads to the development of motor fluctuations and dyskinesia.[1] However, the ELLDOPA study revealed that after only 40 weeks of treatment, both efficacy and levodopa-induced motor complications increased in a dose-dependent fashion in de-novo Parkinson's disease patients who were within 2 years of diagnosis.[4,21] Dyskinesia were reported in 16.5% of patients receiving 600 mg/day of levodopa, which was significantly greater than the 2–3% reported in those receiving 150 mg/day or 300 mg/day. Similarly, motor fluctuations were reported in 30% of patients in the 600 mg/day group, which was significantly greater than the 13–18% reported with the lower doses. These findings have led to two primary treatment strategies related to the use of levodopa in early Parkinson's disease. The first strategy is to initiate treatment with levodopa, particularly in older individuals who may be more susceptible to adverse events related to other agents. Similarly, levodopa may be the initial treatment of choice in patients who are currently employed or because of other aspects of their lifestyle, need maximum control of their symptoms, but rather than increasing dosages above 600 mg/day, another agent such as a dopamine agonist or MAO-B inhibitor could be added in an attempt to delay the onset of motor complications. The second strategy would be to begin treatment with an MAO-B inhibitor or a dopamine agonist, particularly in younger patients, and add levodopa as needed to maintain control of symptoms.

Carbidopa/Levodopa/Entacapone

Carbidopa/levodopa with the addition of the catechol-O-methyltransferase (COMT) inhibitor entacapone was examined as a treatment option in early Parkinson's disease in an attempt to maintain or improve the efficacy of levodopa, but reduce the incidence of dyskinesia. In the FIRST-STEP study,[5] Parkinson's disease patients not on dopaminergic therapy were randomized to either carbidopa/levodopa or carbidopa/levodopa/entacapone. There were no significant differences in the incidence of motor fluctuations or dyskinesia; however, Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living (ADL) and motor scores favored the carbidopa/levodopa/entacapone group. The STRIDE-PD study[6] examined the time to the onset of dyskinesia in Parkinson's disease patients not currently taking levodopa, randomized to either carbidopa/levodopa or carbidopa/levodopa/entacapone. The results indicated that dyskinesia were significantly more frequent with carbidopa/levodopa/entacapone, and they developed significantly earlier than with carbidopa/levodopa. There were no significant differences in motor fluctuations or motor function in the two groups, but dopaminergic adverse events were more common with carbidopa/levodopa/entacapone. Of note, it was shown that regardless of treatment group, dyskinesia were significantly more common in those taking greater than 400 mg/day of levodopa. The findings of these studies suggest that carbidopa/levodopa/entacapone is not a good treatment option in the management of early Parkinson's disease. It should be noted that the negative results of the STRIDE-PD study could be due to several factors, including the possibility that the continuous dopaminergic theory is not correct. A more likely explanation, however, is that the selected dose of levodopa in the carbidopa/levodopa/entacapone group was too high, accounting for the higher frequency of dyskinesia. Further analyses of the STRIDE-PD data suggested that young age at Parkinson's disease onset, higher levodopa dose, low body weight, North American geographic region, women, and more severe UPDRS ADL scores were the strongest predictors of the development of dyskinesia. Similarly, the strongest predictors for the development of motor fluctuations included higher levodopa dose, North American geographic region, women, more severe UPDRS ADL scores, and more severe UPDRS motor scores.[22]

Dopamine Agonists

The efficacy of dopamine agonists in the treatment of early Parkinson's disease has been well documented ( ). Immediate-release pramipexole has been shown to improve UPDRS motor scores by three to six points compared with placebo,[7,8] and twice daily dosing with 0.5 mg and 0.75 mg has been shown to be comparable to 0.5 mg given three times daily (t.i.d.).[9] The extended release (once daily) and immediate release (t.i.d.) formulations of pramipexole have also been shown to be comparable in early disease, with both showing significant improvement compared with placebo.[10] Ropinirole immediate release has been shown to improve UPDRS motor scores by approximately five points compared with placebo.[11] The once daily, prolonged release formulation has not been compared with placebo, but it has been shown to have comparable efficacy to the immediate release formulation (t.i.d.).[23] Rotigotine, the only once daily transdermal patch for Parkinson's disease, has been shown to improve UPDRS motor scores by one to five points compared with placebo.[12,13]

Table 1.  Double-blind, randomized studies of available treatment options for the early management of Parkinson's disease Study Treatment Dosage Study Duration Efficacy (placebo-adjusted change) ELLDOPA [4] carbidopa/levodopa 150 mg/day 24 weeks 3.0 pts UPDRS motor     300 mg/day   5.9 pts UPDRS motor     600 mg/day   7.1 pts UPDRS motor FIRST STEP [5] carbidopa/levodopa/entacapone 25/100/200 t.i.d. 39 weeks 7.0 pts UPDRS motora   carbidopa/levodopa 25/100 t.i.d.   6.2 pts UPDRS motora STRIDE PD [6] carbidopa/levodopa/entacapone 25/100/200 four times daily (q.i.d.) 134 weeks 8.4 pts UPDRS Motor+ADLa   carbidopa/levodopa 25/100 q.i.d.   7.2 pts UPDRS motor+ADLa PSG [7] pramipexole 1.5 mg/day 10 weeks 5.2 pts UPDRS Total     3.0 mg/day   5.1 pts UPDRS Total     4.5 mg/day   5.9 pts UPDRS Total     6.0 mg/day   5.2 pts UPDRS Total Shannon et al. [8] pramipexole 3.8 mg/day (mean) 24 weeks 6.0 pts UPDRS motor PramiBID [9] pramipexole 0.5 twice daily (b.i.d.) 12 weeks 3.2 pts UPDRS motor     0.75 b.i.d.   3.4 pts UPDRS motor     0.5 t.i.d.   3.3 pts UPDRS motor Hauser et al. [10] pramipexole immediate release 3.03 mg/day (mean) 18 weeks 3.2 pts UPDRS motor   pramipexole extended release 3.05 mg/day (mean)   3.2 pts UPDRS motor Adler et al. [11] ropinirole 15.7 mg/day (mean) 6 months 4.7 pts UPDRS motor PSG [12] rotigotine transdermal patch 4.5 mg/day 11weeks 0.9 pts UPDRS motor     9.0 mg/day   1.9 pts UPDRS motor     13.5 mg/day   3.9 pts UPDRS motor     18.0 mg/day   3.8 pts UPDRS motor Watts et al. [13] rotigotine transdermal patch 5.7 mg/day (mean) 6 months 4.8 pts UPDRS motor DATATOP [14] selegiline 10 mg/day 3 months 1.9 pts UPDRS motor Allain et al. [15] selegiline 10 mg/day 3 months 1.0 pts UPDRS motor Palhagen et al. [16] selegiline 10 mg/day 6 months 4.0 pts UPDRS motor TEMPO [17] rasagiline 1.0 mg/day 26 weeks 2.7 pts UPDRS motor     2.0 mg/day   1.7 pts UPDRS motor ADAGIO [18] rasagiline 1.0 mg/day 36 weeks 3.0 pts UPDRS Total     2.0 mg/day   3.2 pts UPDRS Total

ADL, activities of daily living; UPDRS, Unified Parkinson's Disease Rating Scale.

aStudy not placebo controlled.

The occurrence of daytime sleepiness and impulse control disorders should be queried in patients taking dopamine agonists. Daytime sleepiness has been reported to occur in up to 21% of patients[24] and sudden onset of sleep, which can occur while driving, has been reported in approximately 1% of patients taking dopamine agonists.[25] Impulse control disorders such as gambling and compulsive eating, buying or sexual behavior can also occur with dopamine agonist use. In the DOMINION study,[26] over 3000 Parkinson's disease patients were examined and nearly 14% were found to have an impulse control disorder. These behaviors can result from the use of any anti-Parkinson's disease medication, but when the data were further examined, it was revealed that 17% of the patients on a dopamine agonist reported an impulse control problem compared with only 7% on other anti-Parkinson's disease medications. These behaviors generally resolve with the discontinuation of the offending agent.

Whether to initiate treatment with levodopa or a dopamine agonist continues to be a topic of debate. The CALM-PD study with pramipexole[27] and the Ropinirole 056 study[28] compared the initiation of treatment with the respective dopamine agonist or levodopa. In both the studies, the levodopa groups had significantly greater efficacy; however, they also had a significant increase in motor fluctuations and dyskinesia compared with the dopamine agonists. The findings of these studies suggested that initiation of treatment with a dopamine agonist would delay the onset of motor complications compared with the initiation with levodopa, delaying the use of levodopa. However, in a study in which early Parkinson's disease patients receiving up to 600 mg/day of levodopa were randomized to either ropinirole prolonged release or additional levodopa, the groups had comparable motor function, but the group receiving additional levodopa experienced significantly more dyskinesia compared with the group that received ropinirole prolonged release.[29] These studies suggest that the total daily dosage of levodopa is more strongly related to the development of dyskinesia, than whether levodopa or a dopamine agonist is the initial treatment, indicating that combination treatment using lower doses of each medication may be the best approach to achieving the desired efficacy while reducing the risk of motor complications and other adverse events.

MAO-B Inhibitors

MAO-B inhibitors are often used as an initial treatment for Parkinson's disease, particularly in patients with mild symptoms. Although they have been shown to have a significant symptomatic benefit compared with placebo in early Parkinson's disease, the improvements are generally less dramatic than those seen with levodopa or dopamine agonists ( ). Selegiline has been shown to have a one to four-point improvement in UPDRS motor scores compared with placebo in early Parkinson's disease patients.[14–16] A long-term study found that after 5 years, patients in whom selegiline was the initial treatment with levodopa added as needed had better UPDRS scores, fewer motor complications, and required less levodopa than patients who initially received placebo with the addition of levodopa as needed.[30] Similarly, in the TEMPO and ADAGIO studies, rasagiline was shown to have a two to three-point improvement in UPDRS motor scores compared with placebo in early Parkinson's disease patients.[17,18] Using a delayed-start study design, it has also been shown that patients who initially received rasagiline compared with those who initially received placebo and 6–9 months later received rasagiline, had significantly improved UPDRS scores, even after 6.5 years.[18,31,32] It has been suggested that the less dramatic improvement reported with rasagiline compared with other classes of medication may be due to the fact that the patients studied had very mild Parkinson's disease. A subanalysis of the ADAGIO data indicated that when only patients with baseline total UPDRS scores greater than 25.5 points were examined, there was a 6.4-point improvement with rasagiline compared with placebo compared to only a three-point difference when all patients were included in the analysis (mean total UPDRS 20 points).[18] Both selegiline and rasagiline have been studied as potential neuroprotective agents; however, at this time there is insufficient evidence to consider either of them to be definitely neuroprotective.

Table 1.  Double-blind, randomized studies of available treatment options for the early management of Parkinson's disease Study Treatment Dosage Study Duration Efficacy (placebo-adjusted change) ELLDOPA [4] carbidopa/levodopa 150 mg/day 24 weeks 3.0 pts UPDRS motor     300 mg/day   5.9 pts UPDRS motor     600 mg/day   7.1 pts UPDRS motor FIRST STEP [5] carbidopa/levodopa/entacapone 25/100/200 t.i.d. 39 weeks 7.0 pts UPDRS motora   carbidopa/levodopa 25/100 t.i.d.   6.2 pts UPDRS motora STRIDE PD [6] carbidopa/levodopa/entacapone 25/100/200 four times daily (q.i.d.) 134 weeks 8.4 pts UPDRS Motor+ADLa   carbidopa/levodopa 25/100 q.i.d.   7.2 pts UPDRS motor+ADLa PSG [7] pramipexole 1.5 mg/day 10 weeks 5.2 pts UPDRS Total     3.0 mg/day   5.1 pts UPDRS Total     4.5 mg/day   5.9 pts UPDRS Total     6.0 mg/day   5.2 pts UPDRS Total Shannon et al. [8] pramipexole 3.8 mg/day (mean) 24 weeks 6.0 pts UPDRS motor PramiBID [9] pramipexole 0.5 twice daily (b.i.d.) 12 weeks 3.2 pts UPDRS motor     0.75 b.i.d.   3.4 pts UPDRS motor     0.5 t.i.d.   3.3 pts UPDRS motor Hauser et al. [10] pramipexole immediate release 3.03 mg/day (mean) 18 weeks 3.2 pts UPDRS motor   pramipexole extended release 3.05 mg/day (mean)   3.2 pts UPDRS motor Adler et al. [11] ropinirole 15.7 mg/day (mean) 6 months 4.7 pts UPDRS motor PSG [12] rotigotine transdermal patch 4.5 mg/day 11weeks 0.9 pts UPDRS motor     9.0 mg/day   1.9 pts UPDRS motor     13.5 mg/day   3.9 pts UPDRS motor     18.0 mg/day   3.8 pts UPDRS motor Watts et al. [13] rotigotine transdermal patch 5.7 mg/day (mean) 6 months 4.8 pts UPDRS motor DATATOP [14] selegiline 10 mg/day 3 months 1.9 pts UPDRS motor Allain et al. [15] selegiline 10 mg/day 3 months 1.0 pts UPDRS motor Palhagen et al. [16] selegiline 10 mg/day 6 months 4.0 pts UPDRS motor TEMPO [17] rasagiline 1.0 mg/day 26 weeks 2.7 pts UPDRS motor     2.0 mg/day   1.7 pts UPDRS motor ADAGIO [18] rasagiline 1.0 mg/day 36 weeks 3.0 pts UPDRS Total     2.0 mg/day   3.2 pts UPDRS Total

ADL, activities of daily living; UPDRS, Unified Parkinson's Disease Rating Scale.

aStudy not placebo controlled.

Investigational Treatments for Early Parkinson's Disease

One of the primary goals of research on the treatment of early Parkinson's disease focuses on the identification of a disease-modifying or neuroprotective therapy. Multiple treatments with various mechanisms of action have been examined using several different study designs, yet a definitely neuroprotective agent has not been identified.[33] This section will review the published studies of compounds currently under investigation for the symptomatic treatment of early Parkinson's disease ( ).[34,35–39]

Table 2.  Double-blind, randomized studies of investigational treatment options for the early management of Parkinson's disease Study Treatment Dosage Study Duration Efficacy (placebo-adjusted change) APEX-PD [34] IPX066 (carbidopa/levodopa) 145 mg/day t.i.d. 30 weeks 8.2 pts UPDRS motor     245 mg/day t.i.d.   9.1 pts UPDRS motor     390 mg/day t.i.d.   10.3 pts UPDRS motor Stocchi et al. [35] safinamide 0.5 mg/kg (de novo and +DA) 12 weeks 2.0 pts UPDRS motor     1.0 mg/kg (de novo and +DA)   2.7 pts UPDRS motor     0.5 mg/kg (+DA only)   2.6 pts UPDRS motor     1.0 mg/kg (+DA only)   3.3 pts UPDRS motor Stocchi et al. [36] safinamide (+DA) 100 mg/day 24 weeks 2.4 pts UPDRS motor     200 mg/day   0.3 pts UPDRS motor Bronzova et al. [37] pardoprunox 23.8 mg/day (mean) 9 weeks 4.1 pts UPDRS motor Sampaio et al. [38] pardoprunox 6 mg/day 24 weeks 3.2 pts UPDRS motor     12 mg/day   1.9 pts UPDRS motor     12–42mg/day (flex dose)   2.6 pts UPDRS motor Hauser et al. [39] pardoprunox 12–42mg/day (flex dose) 24 weeks 2.4 pts UPDRS motor   pramipexole 1.5–4.5 mg/day (flex dose)   3.1 pts UPDRS motor

ADL, activities of daily living; UPDRS, Unified Parkinson's Disease Rating Scale.

IPX066

IPX066 is a new formulation of carbidopa/levodopa. It is unique as it contains both immediate and extended release components, with the goal of providing immediate benefit in controlling symptoms and then maintaining this benefit over a longer period of time than with the immediate release formulation alone.[39] The APEX-PD study evaluated the efficacy and safety of IPX066 in a randomized, double-blind, placebo-controlled 30-week study of 381 early Parkinson's disease patients not taking levodopa or dopamine agonists with a mean duration of Parkinson's disease approximately 2 years.[34] Patients were equally randomized to receive placebo or 145 mg, 245 mg, or 390 mg of IPX066 in three daily doses approximately every 6 h. There were significant improvements in UPDRS mentation, ADL, motor and total scores, as well as PDQ-39 total scores for all three doses compared with placebo. There were no significant differences in efficacy between the three IPX066 dosages, although there was a trend towards greater efficacy with higher dosages. The most common adverse events were nausea, headache, dizziness, and insomnia, which tended to be more common with the higher two dosages. Dyskinesia occurred in 5.1% of the 390 t.i.d. group, 3.8% of the 245 t.i.d. group, and 2.3% of the 145 t.i.d. group. The authors concluded that the IPX066 145 mg t.i.d. dosage had the best risk–benefit profile of the three dosages tested.

Safinamide

Safinamide has multiple mechanisms of action, including inhibition of MAO-B, dopamine reuptake, and glutamate. Two published randomized, double-blind, placebo-controlled studies have examined the symptomatic effects of safinamide in early Parkinson's disease. In the first study,[35] 172 early Parkinson's disease patients were randomized to either safinamide 0.5 mg/kg or 1.0 mg/kg or placebo. Patients were untreated or receiving a stable dose of a dopamine agonist. There was a significant improvement in UPDRS motor scores for the 1.0 mg/kg group compared with placebo for the whole cohort and also for those on a dopamine agonist. Adverse events were not significantly different between the three groups. In the second 24-week study,[36] safinamide (100 mg or 200 mg) or placebo was added to 270 early Parkinson's disease patients (diagnosis < 5 years) on a stable dosage of a dopamine agonist. The safinamide 100 mg group had a significant improvement in UPDRS motor scores compared with placebo; however, there were no differences between safinamide 200 mg and placebo. Adverse events did not differ between the three groups.

Pardoprunox

Pardoprunox is a 5HT-1A agonist and partial dopamine agonist. In a randomized, double-blind, placebo-controlled study in 139 early Parkinson's disease patients not taking anti-Parkinson's disease medications, pardoprunox significantly improved UPDRS motor scores compared with placebo. The most common adverse events included nausea, dizziness, somnolence, headache, and asthenia.[37] Pardoprunox was examined in two additional randomized, double-blind, placebo-controlled studies, one dose-finding study (n = 468) examined pardoprunox fixed dosages of 6 mg/day or 12 mg/day, a flexible dose of 12–42 mg/day or placebo and a comparator study (n = 334) with pramipexole and a flexible dose of 12–41 mg/day of pardoprunox. In both the studies, UPDRS motor scores were significantly improved with pardoprunox compared with placebo. Adverse events were common and occurred more often with pardoprunox than with placebo. They included somnolence, nausea, and dizziness, most of which occurred during the titration phase of the studies.[38]

Exercise

The potential benefits of exercise early in the course of Parkinson's disease have been increasingly recognized. It is generally believed that patients who maintain an exercise program from the time of diagnosis throughout the disease course will do better long-term; however, at this time, this supposition is based more on clinical experience than controlled trials. In a review of 39 exercise trials conducted in 1827 Parkinson's disease patients at various stages of the disease, it was demonstrated that most studies reported short-term benefits from exercise, particularly for gait, balance, and disability based on UPDRS scores. It was also noted that there is no definitive evidence that one form of exercise is more beneficial than another.[3] In a randomized, delayed-start study of 31 Parkinson's disease patients ranging from newly diagnosed to disease duration of 10 years, patients who started a structured exercise program 6 months prior to the delayed-start group did not show improvements in UPDRS motor scores; however, the early-start group had significant improvements in depression compared with the delayed-start group.[40] In another study of Parkinson's disease patients at various disease stages, tai chi, resistance training, and stretching were compared in a randomized, controlled, 6-month study with exercise sessions every 2 weeks.[41] Improvements in gait, balance, and motor function were seen with both tai chi and resistance training compared with stretching. In addition, tai chi improved postural instability, stride length, and functional reach to a significantly greater degree compared with resistance training. A follow-up study[42] found significant improvements in quality of life with tai chi compared with both resistance training and stretching. A randomized, 16-month study compared balance, physical function, UPDRS, quality of life and walking economy after supervised flexibility/balance/function exercise, supervised aerobic exercise, and home exercise.[43] The only significant differences after 16 months were improvements in UPDRS ADL scores after flexibility/balance/function exercise compared with home exercise and improved walking economy after aerobic exercise compared with both of the other exercise groups. Finally, a pilot study including four de-novo Parkinson's disease patients diagnosed within 1 year examined dopamine D2 receptor availability using [18F]fallypride PET, postural control, and motor function after intensive treadmill exercise, thrice weekly for 8 weeks (n = 2) compared with no exercise (n = 2).[44] Results indicated that dopamine D2 receptor availability was increased and postural control was improved in the two patients undergoing intensive exercise compared with those that did not exercise. These studies suggest the potential improvements in physical function and the possibility of a disease-modifying effect of exercise in early Parkinson's disease. In addition, it has been shown that occupational therapy is beneficial in improving patient-rated performance of ADLs.[45] Additional, larger, controlled studies are necessary to determine the impact of exercise, physical, and occupational therapy in early Parkinson's disease and to determine the type of exercise or therapy that might be most effective.

Conclusion

The goal in the treatment of early Parkinson's disease is to provide effective control of symptoms while delaying the development of motor fluctuations and dyskinesia. Using the currently available treatment options, treatment strategies for early Parkinson's disease have evolved to focus more on maintaining lower daily doses of levodopa and using combination therapy, primarily with dopamine agonists and MAO-B inhibitors, in an attempt to delay the development of motor complications. Research is ongoing to identify new symptomatic and neuroprotective treatment options for early Parkinson's disease, including new dopaminergic compounds as well as those that do not focus directly on dopamine depletion. Several studies have focused on the potential benefits of earlier exercise intervention. Further research is needed to identify a definitely neuroprotective agent for Parkinson's disease, to develop new treatment options with more consistent benefit and fewer adverse events including motor complications, and to determine the full spectrum of benefits achieved with exercise, the most beneficial form of exercise in early Parkinson's disease and the potential of exercise to have a disease-modifying effect.

Key Points
  • Studies suggest that maintaining lower daily dosages of levodopa (<600 mg/day) may be more important in delaying the onset of motor complications, regardless of initiation with levodopa or another available agent.

  • IPX066 is a new formulation of carbidopa/levodopa that has been shown to provide benefit comparable to or greater than that reported with existing compounds with a reduced incidence of dyskinesia compared with that reported with available levodopa preparations.

  • Safinamide and pardoprunox are under investigation for the treatment of early Parkinson's disease and are unique in that they have mechanisms of action affecting more than just dopamine depletion.

  • Earlier implementation of regular and sustained exercise may improve motor function, depression, and quality of life.

  • Further research is needed to confirm early data suggesting that exercise may have a disease-modifying effect in addition to improving physical function.

References
  1. Olanow CW, Stern MB, Sethi K. The scientific and clinical basis for the treatment of Parkinson disease (2009). Neurology 2009; 72 (21 Suppl 4):S1–136.

  2. Fox SH, Katzenschlager R, Lim SY, et al. The movement disorder society evidence-based medicine review update: treatments for the motor symptoms of Parkinson's disease. Mov Disord 2011; 26 (Suppl 3):S2–41.

  3. Tomlinson CL, Patel S, Meek C, et al. Physiotherapy versus placebo or no intervention in Parkinson's disease. Cochrane Database Syst Rev 2013; 9:CD002817.

  4. Hauser RA, Auinger P, Oakes D. Levodopa response in early Parkinson's disease. Mov Disord 2009; 24:2328–2336.

  5. Hauser RA, Panisset M, Abbruzzese G, et al. Double-blind trial of levodopa/carbidopa/entacapone versus levodopa/carbidopa in early Parkinson's disease. Mov Disord 2009; 24:541–550.

  6. Stocchi F, Rascol O, Kieburtz K, et al. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann Neurol 2010; 68:18–27.

  7. Parkinson Study GroupSafety and efficacy of pramipexole in early Parkinson disease. A randomized dose-ranging study. JAMA 1997; 278:125–130.

  8. Shannon KM, Bennett JP Jr, Friedman JH. Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson's disease. The Pramipexole Study Group. Neurology 1997; 49:724–728.

  9. Kieburtz K. Parkinson Study Group PramiBID InvestigatorsTwice-daily, low-dose pramipexole in early Parkinson's disease: a randomized, placebo-controlled trial. Mov Disord 2011; 26:37–44.

  10. Hauser RA, Schapira AH, Rascol O, et al. Randomized, double-blind, multicenter evaluation of pramipexole extended release once daily in early Parkinson's disease. Mov Disord 2010; 25:2542–2549.

  11. Adler CH, Sethi KD, Hauser RA, et al. Ropinirole for the treatment of early Parkinson's disease. The Ropinirole Study Group. Neurology 1997; 49:393–399.

  12. Parkinson Study GroupA controlled trial of rotigotine monotherapy in early Parkinson's disease. Arch Neurol 2003; 60:1721–1728.

  13. Watts RL, Jankovic J, Waters C, et al. Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology 2007; 68:272–276.

  14. Parkinson Study GroupEffect of deprenyl on the progression of disability in early Parkinson's disease. The Parkinson Study Group. N Eng J Med 1989; 321:1364–1371.

  15. Allain H, Pollak P, Neukirch HC. Symptomatic effect of selegiline in de novo Parkinsonian patients. The French Selegiline Multicenter Trial. Mov Disord 1993; 8 (Suppl 1):S36–40.

  16. Palhagen S, Heinonen EH, Hagglund J, et al. Selegiline delays the onset of disability in de novo parkinsonian patients. Swedish Parkinson Study Group. Neurology 1998; 51:520–525.

  17. Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO study. Arch Neurol 2002; 59:1937–1943.

  18. Olanow CW, Rascol O, Hauser R, et al. A double-blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med 2009; 361:1268–1278.

  19. Lyons KE, Pahwa R. Pfeiffer RF, Wszolek ZK, Ebadi M. Amantadine. Parkinson's Disease, 2nd Edition Boca Raton, FL:CRC Press; 2013. 819–824.

  20. Oertel WH, Berardelli A, Bloem BR. Gilhus NE, Barnes MP, Brainin M, et al. Early (uncomplicated) Parkinson's disease. European Handbook of Neurological Management. I 2nd ed.Oxford, UK:Wiley-Blackwell Publishing; 2011. 217–236.

  21. Parkinson Study GroupLevodopa and the progression of Parkinson's disease. N Engl J Med 2004; 351:2498–2508.

  22. Olanow CW, Kieburtz K, Rascol O, et al. Factors predictive of the development of levodopa-induced dyskinesia and wearing-off in Parkinson's disease. Mov Disord 2013; 28:1064–1071.

  23. Stocchi F, Hersh BP, Scott BL, et al. Ropinirole 24-h prolonged release and ropinirole immediate release in early Parkinson's disease: a randomized, double-blind, noninferiority crossover study. Curr Med Res Opin 2008; 24:2883–2895.

  24. Comella CL. Sleep disorders in Parkinson's disease: an overview. Mov Disord 2007; 22 (Suppl 17):S367–S373.

  25. Paus S, Brecht HM, Koster J, et al. Sleep attacks, daytime sleepiness, and dopamine agonists in Parkinson's disease. Mov Disord 2003; 18:659–667.

  26. Weintraub D, Koester J, Potenza MN, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol 2010; 67:589–595.

  27. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 2004; 61:1044–1053.

  28. Rascol O, Brooks DJ, Korczyn AD, et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000; 342:1484–1491.

  29. Watts RL, Lyons KE, Pahwa R, et al. Onset of dyskinesia with adjunct ropinirole prolonged-release or additional levodopa in early Parkinson's disease. Mov Disord 2010; 25:858–866.

  30. Palhagen S, Heinonen E, Hagglund J, et al. Selegiline slows the progression of the symptoms of Parkinson disease. Neurology 2006; 66:1200–1206.

  31. Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004; 61:561–566.

  32. Hauser RA, Lew MF, Hurtig HI, et al. Long-term outcome of early versus delayed rasagiline treatment in early Parkinson's disease. Mov Disord 2009; 24:564–573.

  33. Hart RG, Pearce LA, Ravina BM, et al. Neuroprotection trials in Parkinson's disease: systematic review. Mov Disord 2009; 24:647–654.

  34. Pahwa R, Lyons KE, Hauser RA, et al. Randomized trial of IPX066, carbidopa/levodopa extended release, in early Parkinson's disease. Parkinsonism Relat Disord 2014; 20:142–148.

    ** This is the first clinical trial demonstating the safety and efficacy of IPX066, a new extended release levodopa formulation, in the treatment of early Parkinson's disease. The results of this study suggest efficacy comparable or superior to available treatment options, while reporting a lower incidence of dyskinesia.

  35. Stocchi F, Arnold G, Onofrj M, et al. Improvement of motor function in early Parkinson disease by safinamide. Neurology 2004; 63:746–748.

  36. Stocchi F, Borgohain R, Onofrj M, et al. A randomized, double-blind, placebo-controlled trial of safinamide as add-on therapy in early Parkinson's disease patients. Mov Disord 2012; 27:106–112.

  37. Bronzova J, Sampaio C, Hauser RA, et al. Double-blind study of pardoprunox, a new partial dopamine agonist, in early Parkinson's disease. Mov Disord 2010; 25:738–746.

  38. Sampaio C, Bronzova J, Hauser RA, et al. Pardoprunox in early Parkinson's disease: results from 2 large, randomized double-blind trials. Mov Disord 2011; 26:1464–1476.

  39. Hauser RA, Ellenbogen AL, Metman LV, et al. Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson's disease. Mov Disord 2011; 26:2246–2252.

  40. Park A, Zid D, Russell J, et al. Effects of a formal exercise program on Parkinson's disease: a pilot study using a delayed start design. Parkinsonism Relat Disord 2014; 20:106–111.

  41. Li F, Harmer P, Fitzgerald K, et al. Tai chi and postural stability in patients with Parkinson's disease. N Engl J Med 2012; 366:511–519.

  42. Li F, Harmer P, Liu Y, et al. A randomized controlled trial of patient-reported outcomes with tai chi exercise in Parkinson's disease. Mov Disord 2014; 29:539–545.

  43. Schenkman M, Hall DA, Baron AE, et al. Exercise for people in early- or mid-stage Parkinson disease: a 16-month randomized controlled trial. Phys Ther 2012; 92:1395–1410.

  44. 44 Fisher BE, Li Q, Nacca A, et al. Treadmill exercise elevates striatal dopamine D2 receptor binding potential in patients with early Parkinson's disease. Neuroreport 2013; 24:509–514.

    ** This pilot study provides early evidence suggesting that exercise may not only improve motor function, but may also have neuroprotective capabilities in early Parkinson's disease.

  45. Sturkenboom IH, Graff MJ, Hendriks JC, et al. Efficacy of occupational therapy for patients with Parkinson's disease: a randomised controlled trial. Lancet Neurol 2014; 13:557–566.

 

Curr Opin Neurol. 2014;27(4):442-449. © 2014  Lippincott Williams & Wilkins
 

http://www.medscape.com/viewarticle/829974?src=wnl_edit_tpal&uac=66422BV

 

Share this post


Link to post
Share on other sites

I'm bumping this up because it is a good read. I'm surprised there wasn't any response to it.

Share this post


Link to post
Share on other sites

Thanks, Musicman, I thought it was very good, too. I've worked with Dr. Pahwa and Dr. Lyons in the past, and they are both excellent and inspiring researchers.

 

But the article is quite long, and somewhat technical, which may put people off. Glad you resurrected it!

Edited by Kathrynne Holden, MS

Share this post


Link to post
Share on other sites