Redefining Treatment Success in Patients With Parkinson’s Disease
BUILDING AN EFFECTIVE TREATMENT STRATEGY FOR PD
The primary goal of current pharmacologic therapy for PD is to replenish depleted stores of dopamine either directly or indirectly through administration of levodopa with dopa-decarboxylase inhibitors (DDIs) and catechol-O-methyltransferase (COMT) inhibitors, dopamine agonists, or MAO-B inhibitors (Figure 4).11,15 Since its emergence in the late 1960s as a key advance in the treatment of PD, dopamine replacement therapy with levodopa is still regarded as the most effective treatment for PD. All patients with PD will most likely require therapy with levodopa at some point during the course of their disease. However, because levodopa is rapidly metabolized in the periphery by dopa-decarboxylase before it crosses the blood brain barrier, it is typically administered in combination with a peripheral DDI (eg, carbidopa, benserazide) to reduce this peripheral conversion and increase availability of levodopa in the brain.15 Although levodopa effectively treats the hallmark clinical motor features of PD, many patients ultimately develop dyskinesia (ie, abnormal involuntary movements) and motor fluctuations. Dyskinesia is related to age and to the dose and duration of levodopa treatment, with younger patients and those with more advanced disease at greater risk for developing this adverse event. Motor fluctuations that occur when the effects of a therapeutic dose wane, allowing symptoms to return in advance of the next dose, are termed the “wearing off” effect.15 Another form of motor fluctuation known as the “on/off effect” is characterized by the sudden and unpredictable cycling between periods of normal and poor motor function. Because of these adverse events, some treatment guidelines recommend delaying levodopa therapy as long as possible to minimize the risk of associated motor complications.15
Figure 4. Current pharmacologic therapies for PD and their potential sites of action in the central nervous system. COMT, catechol-O-methyltransferase; MAO-B, monoamine oxidase-B; PD, Parkinson’s disease.
Catechol-O-methyltransferase inhibitors (eg, entacapone, tolcapone) reduce the breakdown of levodopa in the periphery, thus allowing increased concentrations of levodopa to reach the brain for conversion to dopamine.15 Because they increase peripheral dopamine concentrations when administered with levodopa, COMT inhibitors are associated with adverse events similar to levodopa, including dyskinesia, nausea, and vomiting.
Dopamine receptor agonists were originally developed as adjunct therapy to levodopa to treat motor fluctuations, but the more recently introduced nonergot agonists are approved for initial monotherapy as well and are often administered as part of a treatment strategy designed to delay initiation of levodopa therapy.11,12 Clinical studies have demonstrated that when administered as monotherapy or as adjunct therapy to levodopa, pramipexole, ropinirole, and rotigotine allow reduced administration of levodopa, improve motor symptoms, and improve activities of daily living in patients who initiate therapy early.11,12,15 However, treatment with dopamine agonists is associated with adverse events, including postural hypotension, somnolence, hallucinations, and impulse-control disorders.
Monoamine oxidase-B inhibitors (eg, selegiline, rasagiline) block the breakdown of dopamine to dihydroxyphenylacetic acid in the brain, resulting in an increased supply of dopamine.11 As a result, inhibition of MAO-B can increase the dopaminergic response without requiring an increase in levodopa dosage. Treatment with MAO-B inhibitors has also been employed by some neurologists as a potential disease-modifying strategy. In prospective, double-blind, controlled trials, treatment with first-generation MAO-B inhibitor selegiline delayed the progression of disability in patients who had not received previous treatment for PD.15 However, selegiline is metabolized to amphetamine and methamphetamine metabolites, which may induce sleep disturbances and hallucinations in susceptible patients.40
Rasagiline, a second-generation MAO-B inhibitor, is distinguished from selegiline by its lack of amphetamine metabolites and broader clinical evidence base for efficacy as monotherapy in early-stage PD. Results from a randomized, double-blind clinical trial conducted in 404 patients with early-stage PD suggested that monotherapy with rasagiline 1 or 2 mg/d resulted in a greater reduction in UPDRS scores compared with placebo over a 26-week treatment period.41 In the second phase of this study, the placebo group was switched to rasagiline 2 mg/d for 6 months, while the other 2 groups continued receiving rasagiline 1 or 2 mg/d.42 Follow-up at 12 months showed a persistent difference between groups, favoring the group taking rasagiline for the entire year. Patients in the rasagiline groups showed less decline, according to UPDRS scores, than those in the delayed treatment group. In a similar delayed-start study, 1176 patients with untreated early-stage PD were randomized to receive rasagiline 1 or 2 mg/d for 72 weeks or placebo for 36 weeks followed by rasagiline 1 or 2 mg/d for 36 weeks.43 Results from this study are expected in late 2008. These clinical trials suggest that rasagiline may slow progression of disability, as measured by UPDRS scores, when used as monotherapy in early-stage PD.
In addition, results from clinical studies have demonstrated the efficacy of rasagiline in reducing “off” time in patients with levodopa-induced motor fluctuations and dyskinesia.16 The safety profile of rasagiline is comparable to placebo.40 When rasagiline is used as monotherapy and as adjunct therapy to levodopa, the common adverse events are dopaminergic in nature and similar to those seen with other adjunctive agents for PD. There are a number of drugs that are contraindicated for use with MAO-B inhibitors, and patients who receive treatment with rasagiline should avoid foods that contain high concentrations of tyramine.
The traditional approach to treatment of early-stage PD is to delay treatment until symptoms substantially impair the patient’s ability to function.21 However, the results of several important clinical studies suggest that early treatment may improve long-term patient outcomes. Additionally, an early diagnosis may offer the opportunity to administer disease-modifying therapies, once these are identified. A current hypothesis is that administering dopamine replacement therapy early in PD may enhance endogenous compensatory mechanisms and restore dysfunctional dopaminergic signaling cascades.21
The overall goal of PD therapy is transitioning from control of neurologic symptoms to modification of disease progression. Emerging therapeutic agents have demonstrated capacity for neuroprotection in cell culture and animal studies, which, if this capacity successfully translates to humans, may ultimately lead to improved long-term patient outcomes and overall treatment success.12 Evidence-based guidelines put forth by the American Academy of Neurology (AAN) and the MDS conclude that MAO-B inhibitors provide symptomatic benefit as initial monotherapy in early-stage PD and may be considered as initial therapy before administration of dopaminergic agonists.44,45 The MAO-B inhibitor rasagiline, dopaminergic agonists pergolide, pramipexole, ropinirole, and apomorphine, and the COMT inhibitors entacapone and tolcapone are considered efficacious in reducing levodopa-induced motor fluctuations and dyskinesia.16 The AAN practice parameter recommends rasagiline and entacapone at level A for reducing “off” time in patients with PD, due to the high quality of the evidence for the effectiveness of these drugs in treating motor fluctations.16 Pergolide, pramipexole, ropinirole, and tolcapone received a level B recommendation. The United Kingdom’s National Institute for Health and Clinical Excellence guidelines do not identify a first-choice option for early-stage PD, but dopaminergic agonists and MAO-B inhibitors are recommended as possible first choices for symptomatic treatment.46
