What makes UpToDate so powerful?

  • over 10,000 topics
  • 22 specialties
  • 5,700 physician authors
  • evidence-based recommendations
See more sample topics
Find Patient Print
0 Find synonyms

Find synonyms Find exact match

Pharmacologic treatment of Parkinson disease
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
Pharmacologic treatment of Parkinson disease
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2016. | This topic last updated: Apr 16, 2015.

INTRODUCTION — The array of pharmacologic and surgical treatments available for the treatment of idiopathic (or Lewy body) Parkinson disease (PD) is broader than for any other degenerative disease of the central nervous system. Management of individual patients requires careful consideration of a number of factors, including the patient's symptoms and signs, age, stage of disease, degree of functional disability, and level of physical activity and productivity. Treatment can be divided into pharmacologic, nonpharmacologic, and surgical therapy.

The pharmacologic treatment of PD can be further divided into neuroprotective and symptomatic therapy. In practice, nearly all of the available treatments are symptomatic in nature and do not appear to slow or reverse the natural course of the disease. However, several potential neuroprotective agents for PD have shown some promise in animals and/or humans and are undergoing further investigation. Neuroprotective therapy for PD is discussed in greater detail separately. (See "Neuroprotective therapy for Parkinson disease".)

The routine medical management of PD is reviewed here. The nonpharmacologic management of PD, including education, support, exercise, and nutrition, is discussed separately. (See "Nonpharmacologic management of Parkinson disease".)

Treatment of advanced PD, particularly the complications associated with long-term levodopa therapy, and management of the comorbid problems including daytime sleepiness, hallucinations, and psychosis, are reviewed elsewhere. (See "Motor fluctuations and dyskinesia in Parkinson disease" and "Surgical treatment of Parkinson disease" and "Management of comorbid problems associated with Parkinson disease".)

Correct diagnosis is fundamental to the appropriate therapy of PD, although the same menu of antiparkinson drugs is used to treat all of the various parkinsonian syndromes. The diagnosis of PD is reviewed in detail separately. (See "Diagnosis and differential diagnosis of Parkinson disease".)

SYMPTOMATIC THERAPY — The decision to initiate symptomatic medical therapy in patients with PD is determined by the degree to which the patient is functionally impaired. The timing of this decision varies greatly among patients but is influenced by a number of factors, including [1,2]:

The effect of disease on the dominant hand

The degree to which the disease interferes with work, activities of daily living, or social and leisure function

The presence of significant bradykinesia or gait disturbance

Patient values and preferences regarding the use of medications

The major drugs available for the treatment of PD motor symptoms include:


Dopamine agonists

Monoamine oxidase (MAO) B inhibitors

Anticholinergic agents


Catechol-O-methyl transferase (COMT) inhibitors

The following general principles can be used to guide the choice of therapy in symptomatic PD:

Levodopa is the most effective drug for the symptomatic treatment of PD and is the drug of first choice if symptoms, particularly those related to bradykinesia, become intrusive or troublesome. In addition, levodopa should be introduced when akinetic symptoms become disabling for patients receiving other antiparkinsonian drugs. (See 'Levodopa' below.)

The dopamine agonists may be employed either as monotherapy in early PD or in combination with other antiparkinsonian drugs for treatment of more advanced disease. They are ineffective in patients who show no response to levodopa. While dopamine agonists possibly delay the need to initiate levodopa therapy, their use is associated with an increased risk of impulse control disorders. (See 'Dopamine agonists' below.)

Either levodopa or a dopamine agonist can be used initially for patients who require symptomatic therapy for PD [2,3]. Given the potential that dopamine agonists may be associated with fewer motor fluctuations than levodopa, and the evidence that there is a higher incidence of levodopa-related dyskinesia in young-onset PD, it is reasonable to start therapy with a dopamine agonist in younger patients (age <65 years), and with levodopa in older patients (age ≥65 years). In practice, while symptoms can be controlled initially with dopamine agonists, few patients with progressive disease can be satisfactorily maintained on dopamine agonist monotherapy for more than a few years before levodopa is needed.

The MAO B inhibitors selegiline and rasagiline may be useful in patients with early PD but have only modest symptomatic benefit as monotherapy. (See 'MAO B inhibitors' below.)

Anticholinergic drugs are most useful as monotherapy in patients under 70 years of age with disturbing tremor who do not have significant bradykinesia or gait disturbance. They also may be useful in patients with more advanced disease who have persistent tremor despite treatment with levodopa or dopamine agonists. Their use in older or demented individuals and those without tremor is strongly discouraged. (See 'Anticholinergics' below.)

Amantadine is a relatively weak antiparkinsonian drug with low toxicity that is most useful in treating younger patients with early or mild PD and perhaps later when dyskinesia becomes problematic. However, toxic side effects are more likely in older patients. (See 'Amantadine' below.)

Low-dose estrogen may be helpful as adjunctive therapy in postmenopausal women (See 'Estrogen' below.).

There are exceptions to these general rules, and all treatments for PD should be individualized. Practitioners should always try to find the lowest but still effective dose of dopaminergic medication, either singly or in combination, for patients with PD, each of whom must be evaluated and managed in a highly individual way.

Swallowing restrictions — Most patients with PD can go without antiparkinson medications for a brief period (ie, <24 hours) when oral intake is temporarily restricted (eg, when perioperative or periprocedural), or when seriously ill. In patients who are critically ill and bedbound, the parkinsonian symptoms are typically overshadowed by the burden of other medical problems, and antiparkinson medications may not provide any clear benefit. However, sudden withdrawal or dose reduction of antiparkinson medications can rarely precipitate the parkinsonism-hyperpyrexia syndrome. (See 'Parkinsonism-hyperpyrexia syndrome' below.)

When treatment is still desired for patients who are restricted to take nothing by mouth (nil per os; NPO), options include transdermal rotigotine and apomorphine by injection or continuous infusion. The use of apomorphine requires a test dose prior to ongoing treatment (see 'Dopamine agonists' below). For patients with a nasogastric feeding tube, levodopa tablets can be crushed and given through the tube [4]. For patients with dysphagia, orally disintegrating carbidopa-levodopa (Parcopa) is a potential treatment option. (See 'Formulations' below.)

Parkinsonism-hyperpyrexia syndrome — There have been reports of patients with PD who developed neuroleptic malignant syndrome in the context of sudden withdrawal or dose reductions of levodopa or dopamine agonists, and rarely amantadine, as well as with switching from one agent to another. In this context, the condition has been termed the parkinsonism-hyperpyrexia syndrome (see "Neuroleptic malignant syndrome", section on 'Antiparkinson medication withdrawal'). Prompt recognition and treatment are important, as severe cases and even fatalities have been reported [5,6].

Management of parkinsonism-hyperpyrexia syndrome involves replacing antiparkinson medications at the dose that was used prior to the onset of the syndrome [6]. Levodopa and dopamine agonists can be given orally or via nasogastric tube. Levodopa can also be given intravenously (50 to 100 mg infused over three hours, repeated four times daily) if both oral and nasogastric feeding are contraindicated; options for dopamine agonists include transdermal rotigotine and apomorphine by injection or continuous infusion. The use of apomorphine requires a test dose prior to ongoing treatment. (See 'Dopamine agonists' below.)

In addition to replacing antiparkinson medications, patients with significant hyperthermia and rigidity should be admitted to an intensive care unit setting and undergo aggressive supportive care as well as monitoring for potential dysautonomia and other complications (see "Neuroleptic malignant syndrome", section on 'Supportive care'). For patients with severe symptoms who do not respond to restarting antiparkinson medications and supportive care within the first day or two, additional though unproven measures to consider include the use of dantrolene, bromocriptine, and/or amantadine. (See "Neuroleptic malignant syndrome", section on 'Specific treatments'.)

LEVODOPA — Levodopa (L-dopa) is well-established as the most effective drug for the symptomatic treatment of idiopathic or Lewy body PD [2,7]. It is particularly effective for the management of bradykinetic symptoms and should be introduced when these become intrusive or troublesome or are uncontrolled by other antiparkinsonian drugs. Tremor and rigidity can also respond to levodopa therapy, but postural instability is less likely to do so.

As noted previously (see 'Symptomatic therapy' above), either levodopa or a dopamine agonist can be used initially for patients who require symptomatic therapy for PD. It is reasonable to initiate therapy with a dopamine agonist in younger patients (age <65 years), and with levodopa in older patients (age >65 years). However, there are exceptions to these general rules, and all treatments should be individualized. Levodopa is the drug of choice if symptoms, particularly those related to bradykinesia, seriously threaten the patient's lifestyle.

Formulations — Levodopa is combined with a peripheral decarboxylase inhibitor to block its conversion to dopamine in the systemic circulation and liver (before it crosses the blood-brain barrier) in order to prevent nausea, vomiting, and orthostatic hypotension. In the United States, the decarboxylase inhibitor is carbidopa. The combination drug carbidopa-levodopa (immediate-release Sinemet) is available in tablets of 10/100, 25/100, and 25/250 mg, with the numerator referring to carbidopa and the denominator referring to the levodopa dose. An immediate-release formulation of carbidopa-levodopa (Parcopa) is available that dissolves on the tongue and can be taken without water [8,9]; its time of onset of action is not different from Sinemet.

In some countries, benserazide is the peripheral decarboxylase inhibitor. The combination drug benserazide-levodopa (Madopar or Prolopa) is available in 25/100 and 50/200 mg tablets. In many countries, both carbidopa-levodopa (eg, Sinemet) and benserazide-levodopa (eg, Prolopa) are marketed.

Controlled-release formulations of carbidopa-levodopa and benserazide-levodopa are available as Sinemet CR and Madopar HBS, respectively. Compared with regular levodopa, the absorption of the controlled-release formulations is approximately 70 percent.

Dosing — Treatment should begin with small doses, such as carbidopa-levodopa (Sinemet) 25/100 mg, one-half tablet two to three times daily with meals. Tolerance for the appropriate starting dose must be assessed individually. Once initiated without side effects, the total daily dose of carbidopa-levodopa can be titrated carefully upward over several weeks to a full tablet of 25/100 mg three times daily as tolerated. Older adults or those with dementia should begin with smaller doses and slower titration because of their increased susceptibility to psychiatric side effects.

The usual practice is to titrate to the lowest levodopa dose that produces a useful clinical response. This varies from patient to patient, but at the start it is typically in the vicinity of 300 to 600 mg of levodopa daily. The vast majority of patients with idiopathic PD will enjoy a significant therapeutic response to moderate doses of levodopa (300 to 600 mg daily). Complete absence of response to a levodopa dose of 1000 to 1500 mg/day suggests that the original diagnosis of PD may be incorrect and that one of the other parkinsonian syndromes, such as multiple system atrophy, progressive supranuclear palsy, or vascular parkinsonism should be considered. (See "Diagnosis and differential diagnosis of Parkinson disease".)

Levodopa should not be stopped abruptly because sudden withdrawal has been associated (rarely) with a syndrome resembling neuroleptic malignant syndrome or akinetic crisis (see 'Parkinsonism-hyperpyrexia syndrome' above).

Controlled or sustained release levodopa preparations are less completely absorbed and require a dose up to 30 percent higher to achieve an equivalent clinical effect. The peak clinical effect of each tablet is typically less than for immediate release preparations, since controlled release formulations reach the brain more slowly over time. This presents a disadvantage in assessing the response of patients just initiating therapy. As a result, it is recommended that therapy be started with an immediate release preparation with a subsequent switch to controlled release if desired for convenience purposes. Both the immediate and the controlled release formulations appear to maintain a similar level of symptom control after several years of use [10].

Patients taking levodopa for the first time should take each dose with a meal or snack to avoid nausea, a common early side effect. Patients with more advanced disease, especially those with motor fluctuations, often notice that a dose of levodopa is more effective if taken on an empty stomach 30 minutes before or one hour after meals due to reduced competition with other amino acids for gastrointestinal absorption.

Small starting doses of levodopa of less than 25/100 mg three times daily combined with a decarboxylase inhibitor (eg, Sinemet, Madopar, or Prolopa) are more likely to cause nausea because of inadequate amounts of carbidopa; this can be managed by administering supplemental doses of carbidopa or by use of antiemetics such as trimethobenzamide or domperidone (not available in the United States) taken prior to Sinemet. Phenothiazine antiemetics such as prochlorperazine and metoclopramide should be avoided because they are dopamine receptor blockers that can aggravate parkinsonian symptoms.

Adverse effects — Nausea, somnolence, dizziness, and headache are among the more common early side effects that may accompany treatment with levodopa, but they are not likely to be serious in most patients. More serious adverse reactions to levodopa (mainly in older patients) may include confusion, hallucinations, delusions, agitation, psychosis, and orthostatic hypotension.

Levodopa may also induce a mild to moderate elevation in serum homocysteine levels [11-14], which in turn may be associated with an increased risk of hip fractures in older adults. (See "Osteoporotic fracture risk assessment", section on 'Possible risk factors'.)

In addition, there is accumulating evidence suggesting that levodopa exposure in patients with idiopathic PD is associated with low serum levels of vitamin B12, elevated methylmalonic acid levels, and a higher than expected incidence of sensorimotor peripheral neuropathy [15-18].

Compulsive dopaminergic drug use has been reported in patients taking dopamine agonists, typically in conjunction with levodopa therapy. However, it is unclear that these behavioral issues arise with any frequency with levodopa monotherapy. (See 'Dopaminergic dysregulation syndrome' below.)

Motor fluctuations — A substantial number of patients with PD develop levodopa-induced complications within several years of starting levodopa. These include motor fluctuations (the wearing-off phenomenon), involuntary movements known as dyskinesia, abnormal cramps and postures of the extremities and trunk known as dystonia, and a variety of complex fluctuations in motor function [19,20]. It is estimated that such motor complications occur in at least 50 percent of patients after 5 to 10 years of treatment [1]. (See "Motor fluctuations and dyskinesia in Parkinson disease".)

The risk of motor complications increases with a younger age at PD onset and with higher levodopa doses, as supported by the following reports:

In the large group of patients with early PD studied in the DATATOP study, motor complications occurred in 30 percent after only two years of treatment with levodopa [21]. However, in a study of early PD, the prevalence of motor complications was only 20 percent after five years of treatment with levodopa given in relatively low doses [22].

Several observational studies have noted that motor complications are more common in patients with young-onset PD compared with older onset [23,24]. As an example, in a population-based study that compared patients who were 40 to 59 years of age at PD onset with those who were older than 70 years of age at PD onset, the corresponding five-year incidence of dyskinesia was 50 versus 16 percent [24].

In an analysis of data from the STRIDE-PD study, the strongest risk factors for the development of dyskinesia and wearing-off phenomenon were young age at onset and higher levodopa doses [25].

Retrospective data from a study of the effect of pramipexole and levodopa on early PD (the CALM-PD study) suggest that the earlier occurrence of motor fluctuations in the course of PD is associated with higher cumulative levodopa doses and higher cumulative levodopa-equivalent doses (ie, levodopa plus the dopamine agonist pramipexole) [26]. In contrast, prospective data from the same study suggest that a later onset of motor fluctuations in PD is associated with initial treatment with pramipexole rather than levodopa [27,28]. The authors concluded that "higher doses of dopaminergic medications than necessary to effectively control parkinsonian symptoms should be avoided," but noted that some patients with worse (ie, more rapidly progressive) disease may require high doses of dopaminergic medications to manage symptoms and therefore may be at greater risk for the development of motor complications [26]. However, they noted that motor complications do not necessarily cause clinically significant functional impairment and can potentially be managed.

Despite these reports, there is increasing evidence that the choice of initial therapy for PD, whether levodopa, dopamine agonist, or monoamine oxidase (MAO) B inhibitor, has little impact on the long-term outcome of PD in terms of motor fluctuations and dyskinesia [29-31].

The increase in motor fluctuations over time is most likely due to progressive degeneration of nigrostriatal dopamine terminals, which increasingly limits the normal physiologic uptake and release of dopamine, thereby leading to reduced buffering of the natural fluctuations in plasma levodopa levels that occur due to its 90-minute pharmacologic half-life [1]. Controlled release preparations can be useful for management of these fluctuations, though on occasion the less predictable onset of effect with controlled release levodopa makes motor fluctuations more difficult to control. In one report, the use of Sinemet CR three times daily (in an effort to provide more continuous stimulation of dopamine receptors) from the start of therapy was not associated with fewer motor complications compared with immediate release Sinemet [22].

There has been longstanding concern among some clinicians that levodopa causes motor fluctuations and dyskinesia by its potential to promote oxidative stress and accelerated neurodegeneration, rather than by the change in levodopa pharmacodynamics that occurs with natural progression of the underlying disease [32,33]. Therefore, it is commonly proposed that the initiation of levodopa be delayed until symptoms significantly interfere with function. Others contend, however, that there is no convincing evidence that levodopa is itself responsible for late motor complications, and that delay of treatment unnecessarily deprives patients of therapeutic benefit early in the disease, when the potential for sustained improvement is greatest [34].

Given these data, practitioners should always try to find the lowest but still effective dose of dopaminergic medication, either singly or in combination, for patients with PD, each of whom must be evaluated and managed according to his or her individual needs.

Acute akinesia is a sudden exacerbation of PD characterized by an akinetic state that lasts for several days and does not respond to treatment with antiparkinson medication. This phenomenon is very different from the more common wearing "off" effects and is discussed separately. (See "Motor fluctuations and dyskinesia in Parkinson disease", section on 'Acute akinesia'.)

Neurotoxic versus neuroprotective effects — The concern that prolonged use of levodopa may directly hasten the degeneration of dopamine neurons in the substantia nigra by promoting the generation of free radicals and oxidative stress is one rationale for delaying the use of levodopa in the treatment of PD [35]. Another more compelling reason for delaying the use of levodopa is to possibly postpone the appearance of motor complications such as dyskinesia and motor fluctuations. The evidence regarding potential effects of levodopa on dopaminergic neurons is summarized by the following observations:

In vitro, levodopa is toxic to cultured dopamine neurons [36]. In contrast, levodopa does not damage dopamine neurons in tissue culture in presence of glial cells, in normal humans (who do not have PD), or in intact animals [37].

In a retrospective neuropathologic study of patients with PD, the cumulative lifetime dose of levodopa did not correlate with disease pathology as measured by neuronal cell counts in the substantia nigra or by Lewy body density in the cortex and substantia nigra [38].

One experimental study found that levodopa increased neuronal damage in animals with partial injury to dopaminergic neurons [39]. However, this was not confirmed in subsequent reports [40,41].

A 1998 consensus conference reached the following conclusions, which remain relevant today [42]:

There is no evidence that levodopa causes neuronal death in animal models of parkinsonism

The relevance of in vitro studies of levodopa toxicity to clinical use of levodopa is highly uncertain

There is no evidence that chronic administration of levodopa exacerbates the degenerative process in PD

Late motor complications arise due to the combination of progressive degeneration of dopamine neurons and the reversible effects of levodopa administration

Data from the ELLDOPA trial suggest that levodopa, rather than being neurotoxic, either slows the progression of PD or has a prolonged benefit even after the drug has been stopped. The ELLDOPA trial examined 361 patients with newly diagnosed PD and randomly assigned them to either one of three carbidopa-levodopa doses (12.5/50 mg; 25/100 mg; 50/200 mg) given three times daily or to placebo for 40 weeks, followed by withdrawal of treatment for two weeks [43].

At 42 weeks, when underlying motor signs theoretically would be unmasked as a result of the two week washout, all groups assigned to levodopa showed significantly less worsening in the symptoms of parkinsonism, as measured by the Unified Parkinson disease rating scale (UPDRS) (table 1), than did the placebo group [43]. Patients receiving the highest levodopa dose (600 mg/day) had the lowest (better) UPDRS score but, importantly, also had significantly more dyskinesia. Hypertonia, infection, headache, and nausea were also more common than in the placebo group. Therefore, the clinical data suggested, surprisingly, that the use of levodopa for 40 weeks was neuroprotective.

On the other hand, imaging data from a substudy of 116 patients supported observations from two previous studies that levodopa treatment is associated with a greater decline in basal ganglia uptake of dopamine [43]. The substudy used single photon emission computed tomography (SPECT) to assess striatal dopamine by measuring [123I]beta-CIT uptake, and showed that patients taking levodopa had a greater reduction in nigrostriatal dopamine transport compared with those on placebo. Once again, the question of levodopa toxicity versus levodopa-related down regulation of the dopamine transporter receptors could not be resolved.

In conclusion, the debate over the potential neuroprotective versus neurotoxic effects of levodopa remains unresolved [44-46], but the weight of the evidence accumulated to date shows that long term use of levodopa is not a hazard, especially in light of its superiority over all other pharmacotherapies.

Further clinical trials are needed to determine the effects of levodopa on the progression of PD [35]. In the meantime, levodopa remains the most effective therapy for PD, and should be introduced if there is sufficient compromise of quality of life or functional ability to warrant treatment.

DOPAMINE AGONISTS — The dopamine agonists (DAs) are a group of synthetic agents that directly stimulate dopamine receptors. The drugs currently approved by the United States Food and Drug Administration (FDA) include bromocriptine, pramipexole, ropinirole, rotigotine, and injectable apomorphine. Pergolide has been voluntarily withdrawn from the United States market and is best avoided because it is associated with a risk of cardiac valve problems (see 'Valvular heart disease' below).

Apomorphine and lisuride are additional DAs that can be administered parenterally for "rescue therapy" in patients experiencing sudden akinetic episodes. Lisuride is not currently approved in the United States, but is available in Europe. Injectable apomorphine has been approved by the United States FDA for treatment of motor fluctuations in PD [47]. Apomorphine infusion pumps may also be useful, but are not available in the United States. (See "Motor fluctuations and dyskinesia in Parkinson disease", section on 'Dopamine agonists'.)

Unlike carbidopa-levodopa (Sinemet), these drugs are direct agonists that do not require metabolic conversion, do not compete with amino acids for transport across the gut or into the brain, and do not depend upon neuronal uptake and release. An additional advantage over immediate-release forms of levodopa is the longer duration of action of most of these agents.

Monotherapy — Dopamine agonists (DAs) were initially introduced as adjunctive treatment for advanced PD complicated by reduced levodopa response, motor fluctuations, dyskinesia, and other adverse effects of levodopa. However, the hypothetical concern that free radicals generated by the oxidative metabolism of dopamine contribute further to the degeneration of dopaminergic neurons has prompted some investigators, despite lack of conclusive evidence, to advocate the early use of DAs as an levodopa-sparing strategy [48,49].

With this approach, treatment with levodopa can be postponed and saved for a later time in the course of the disease, when disability worsens and the less effective agonists no longer provide adequate benefit. This strategy is based upon the unproven concept that the long-term duration of a given patient's responsiveness to levodopa is finite and that the drug, like money in a savings or retirement account, should be rationed. However, whether reduced responsiveness to levodopa over time is due to a decline in drug response or progression of underlying PD is currently uncertain.

Given the potential that DAs are associated with fewer motor fluctuations and the evidence that there is a higher incidence of levodopa-related dyskinesia in young-onset PD, some experts suggest using DAs as initial treatment for PD in patients younger than age 60, and using the more effective agent levodopa in patients 60 and older [50], although other factors should be weighed in making this treatment decision. In particular, there is evidence that the choice of initial therapy – whether levodopa, dopamine agonist, or monoamine oxidase (MAO) B inhibitor – has little impact on the long-term outcome of PD in terms of motor fluctuations and dyskinesia. (See 'Motor fluctuations' above.)

Effectiveness of dopamine agonists — Controlled trials have shown that the dopamine agonist (DA) drugs, including bromocriptine, pramipexole, and ropinirole, are effective in patients with advanced PD complicated by motor fluctuations and dyskinesia [1]. (See "Motor fluctuations and dyskinesia in Parkinson disease", section on 'Dopamine agonists'.)

In addition, other studies have found that pramipexole, ropinirole, and transdermal rotigotine are effective as monotherapy in patients with early disease [28,51-57]. However, DAs are ineffective in patients who have shown no therapeutic response to levodopa.

The utility of DAs in early PD is supported by the results of a systematic review and meta-analysis published in 2008 that identified 29 eligible trials involving 5247 subjects [58]. Included trials compared DA therapy (with or without levodopa) versus placebo and/or levodopa. The following observations were reported:

In 16 trials that compared a DA (plus or minus supplementation with levodopa) versus levodopa, patients assigned to DA treatment were less likely to develop dyskinesia (odds ratio [OR] 0.51, 95% CI 0.43-0.59), dystonia (OR 0.64, 95% CI 0.51-0.81) or motor fluctuations (OR 0.75, 95% CI 0.63-0.90) than those assigned to levodopa.

In contrast, symptomatic control of PD appeared to be better with levodopa than with DAs. Inconsistent and incomplete data reporting prevented meta-analysis of motor symptom control. However, patients assigned to levodopa had significantly greater improvement in clinician-rated disability in four of the 11 trials that compared DAs with levodopa, while a nonsignificant improvement favoring levodopa was reported in five of the remaining seven trials.

The reduction in motor complications with DAs compared with levodopa is further illustrated by findings from individual trials.

One randomized trial found that the cumulative incidence of dyskinesia over five years was 20 percent in patients assigned to ropinirole (plus or minus supplementation with levodopa) and 45 percent in patients assigned to levodopa [56].

Another randomized trial found a similar 22 percent absolute reduction in the development of dyskinesia and a 16 percent reduction in wearing "off" in patients assigned to pramipexole compared with those assigned to levodopa (figure 1) [28]. On the other hand, patients assigned to levodopa had lower incidences of freezing, somnolence, and leg edema (the latter two attributable to side effects of pramipexole), and had better symptomatic control than those assigned to pramipexole. Both treatments resulted in similar quality of life.

Thus, there is evidence from several clinical trials and a meta-analysis that early DA monotherapy postpones the future onset of motor complications. This may simply be because DAs are less potent than levodopa in their effects on motor function. In support of this, the benefit occurs at the expense of reduced efficacy when compared with levodopa. In practice, while symptoms can be controlled initially with DAs, few patients with progressive disease can be satisfactorily maintained on DA monotherapy for more than a few years before levodopa is needed.

The few studies that have compared the efficacy of various DAs with each other have found either no significant difference [59,60] or only mild superiority of one agent over another [61,62].

Dosing — The DAs generally require administration at least three times a day at maintenance doses:

Bromocriptine is usually started at 1.25 mg twice a day; the dose is increased at two to four week intervals by 2.5 mg a day. Most patients can be managed on 20 to 40 mg daily in three to four divided doses, although total daily doses as high as 90 mg can be used.

Pramipexole is usually started at 0.125 mg three times a day. The dose should be increased gradually by 0.125 mg per dose every five to seven days. Most patients can be managed on total daily doses of 1.5 to 4.5 mg.

Ropinirole is usually started at 0.25 mg three times a day. The dose should be increased gradually by 0.25 mg per dose each week for four weeks to a total daily dose of 3 mg. Most patients can be managed on this dose. After week four, the ropinirole dose may be increased weekly by 1.5 mg a day up to a maximum total daily dose of 24 mg. Benefit most commonly occurs in the dosage range of 12 to 16 mg per day.

Pramipexole and ropinirole are available in sustained release formulations, which are given once daily; these are useful for convenience and for avoiding peaks and troughs in plasma levels.

Transdermal rotigotine is a once-daily patch that is usually started at 2 mg/24 hours and titrated weekly by increasing the patch size in 2 mg/24 hour increments to a dose of 6 mg/24 hours.

Apomorphine may be administered either as intermittent rescue injections or as continuous infusions to treat "off" episodes or levodopa-induced motor fluctuations. A challenge test dose must precede routine use. This is usually done with a 2 mg subcutaneous injection under medical supervision and monitoring of standing and supine blood pressure before the injection, and repeated at 20, 40, and 60 minutes after. Antiemetic therapy (eg, with trimethobenzamide) is initiated three days prior to starting apomorphine and is usually continued for two months before reassessing need. However, the use of apomorphine is contraindicated with ondansetron and other serotonin receptor antagonists commonly used to treat nausea and vomiting, as the combination may cause severe hypotension and loss of consciousness [63]. In addition, dopamine antagonists used to treat nausea and vomiting such as prochlorperazine and metoclopramide should be avoided, as they may reduce the effectiveness of apomorphine.

The usual starting dose for intermittent apomorphine use, if the patient tolerates and responds to the test dose, is 2 mg. The dose may be increased by 1 mg per dose every two to four days to a maximum of 6 mg per dose. The average dosing frequency is three times daily and should not exceed five times a day dosing or a total daily dose of 20 mg.

Dopamine agonists should not be stopped abruptly because sudden withdrawal of DAs has been associated (rarely) with a syndrome resembling neuroleptic malignant syndrome or akinetic crisis (see 'Parkinsonism-hyperpyrexia syndrome' above) and with a stereotyped withdrawal syndrome (see 'Dopamine agonist withdrawal syndrome' below).

Adverse effects of dopamine agonists — Adverse effects caused by dopamine agonists (DAs) are similar to those of levodopa, including nausea, vomiting, sleepiness, orthostatic hypotension, confusion, and hallucinations. Peripheral edema is common with the chronic use of DAs but is rare in patients using levodopa alone. In the systematic review of 29 trials and 5247 patients cited above, those assigned to DA treatment were significantly more likely than patients assigned to levodopa therapy to develop side effects of edema, somnolence, constipation, dizziness, hallucinations, and nausea [58]. In addition, patients assigned to DA therapy were significantly more likely to discontinue treatment due to adverse events (OR 2.49, 95% CI 2.08-2.98).

These adverse effects of DAs can usually be avoided by initiating treatment with very small doses and titrating to therapeutic levels slowly over several weeks. Patients intolerant of one DA may tolerate another. As with all of the antiparkinsonian drugs, older adult and demented patients are much more susceptible to psychiatric side effects.

Accumulating evidence suggests that the use of DAs as a class may lead to compulsive use of dopaminergic drugs and/or impulse control disorders in up to 15 percent of patients taking these drugs (see 'Dopaminergic dysregulation syndrome' below and 'Impulse control disorders' below).

The use of transdermal rotigotine is associated with skin site reactions, typically transient and mild to moderate in severity, but occasionally severe enough to result in discontinuation.

The use of pergolide or cabergoline is associated with a risk of valvular heart disease. (See 'Valvular heart disease' below.)

Adverse events with apomorphine are usually mild and consist predominantly of cutaneous reactions and neuropsychiatric problems [47]. The incidence of these problems is higher in patients receiving continuous infusion than in those receiving intermittent subcutaneous injections. Chest pain, angina, and orthostatic hypotension are more serious problems; orthostasis peaks 20 minutes after dosing and lasts at least 90 minutes. A test dose of apomorphine to establish tolerance and responsiveness is essential prior to routine administration.

Ergot-related side effects such as Raynaud phenomenon, erythromelalgia, and retroperitoneal or pulmonary fibrosis are uncommon with bromocriptine and pergolide, and they do not occur at all with the nonergot agonists ropinirole, pramipexole, and rotigotine.

Dopamine receptor agonists decrease prolactin concentration [64]. Thus, there is a potential for decreased milk production in postpartum women taking these agents, which are contraindicated in women who are breast feeding.

The manufacturer of pramipexole has issued a warning regarding somnolence that can occur abruptly and without premonition, particularly at a dose above 1.5 mg/day. Patients with PD who drive are at particular risk of developing these "sleep attacks" [65]. Patients should be warned of this potential side effect and asked about factors that may increase the risk of drowsiness, such as concomitant sedating medications, sleep disorders, and medications that increase pramipexole levels (eg, cimetidine). (See "Management of comorbid problems associated with Parkinson disease", section on 'Daytime sleepiness'.)

Valvular heart disease — Mounting evidence suggests that treatment with pergolide or cabergoline is associated with a clinically and statistically significant risk of valvular heart disease, with lesions similar to those associated with carcinoid, ergot, and fenfluramine-induced valvular disease [66-72]. The risk of valvular heart disease appears to increase relative to the cumulative dose of pergolide or cabergoline. The mechanism is probably related to pergolide and cabergoline activation of serotonin (5-HT 2B type) receptors expressed on heart valves, which in turn leads to valvular overgrowth [73].

Thus, pergolide and cabergoline should not be used as treatment for PD. In the United States, pergolide was voluntarily withdrawn from the market in March 2007 due to the potential risk of heart valve damage [74].

Dopaminergic dysregulation syndrome — Compulsive use of dopaminergic drugs develops in a small number of patients with PD and has been termed the dopaminergic dysregulation syndrome (DDS) [75].

DDS typically involves male patients with early onset PD who take increasing quantities of dopaminergic drugs despite increasingly severe drug-induced dyskinesia [75,76]. DDS can be associated with a cyclical mood disorder characterized by hypomania or manic psychosis. Tolerance (or frank dysphoria) to the mood elevating effects of dopaminergic therapy develops, and a withdrawal state occurs with dose reduction or withdrawal. Impulse control disorders including hypersexuality and pathologic gambling may accompany DDS [75]. (See 'Impulse control disorders' below.)

A form of complex, prolonged, purposeless, and stereotyped behavior called punding also may be associated with DDS [77].

DDS appears to be uncommon but not rare. In a series of 202 patients with PD, criteria for DDS were fulfilled in seven (3.4 percent) [78]. DDS may occur more frequently with dopaminergic agonists than with levodopa [78], but data are scarce. A small case-control study found that susceptibility factors for DDS included younger age at disease onset, higher novelty seeking personality traits, depressive symptoms, and alcohol intake [79].

Management of DDS is not well studied. Practitioners should limit dopaminergic dose increases when possible, particularly in patients who may have increased susceptibility to DDS. Continuous subcutaneous apomorphine infusions may be useful to suppress off-period dysphoria, and low doses of clozapine or quetiapine may be helpful for some patients [79]. Treatment of psychosis in patients with PD is discussed in detail elsewhere. (See "Management of comorbid problems associated with Parkinson disease", section on 'Psychosis and hallucinations'.)

Impulse control disorders — Dopamine (DA) agonist therapy is associated with an increased risk of impulse control disorders including pathologic gambling, compulsive sexual behavior, or compulsive buying [80-82]. This issue is illustrated by the following reports:

In a Canadian case series of 297 patients with PD, the lifetime prevalence of pathologic gambling, hypersexuality, or compulsive shopping was 13.7 percent in patients on DAs [83]. The lifetime prevalence of pathologic gambling for all patients and for those receiving any DA was 3.4 and 7.2 percent, respectively, compared with a lifetime prevalence of 1.0 percent in the Ontario population [84]. There was a statistically significant association of pathologic gambling and hypersexuality with earlier PD onset and DA therapy [83,84]. In line with earlier retrospective studies [85,86], pathologic gambling did not develop in patients receiving levodopa monotherapy [84]. (See "Overview of gambling disorder".)

Another series of 272 patients with PD found that criteria for impulse control disorders, either anytime during the course of PD or currently active, were met by 6.6 and 4.0 percent of patients, respectively [87]. The frequency of pathologic gambling, compulsive sexual behavior, and compulsive buying anytime during PD were 2.6, 2.6, and 1.5 percent, respectively. On multivariate analysis, significant predictors of an active impulse control disorder were use of a DA and a history of impulse control disorder symptoms before the onset of PD.

Findings from a study that compared recently diagnosed, untreated patients with PD (n = 168) with healthy controls (n = 143) suggest that untreated PD itself is not associated with increased risk of developing impulse control disorders [88].

In a retrospective case series of 11 patients with PD who developed pathologic gambling linked to DA therapy, the pathologic gambling resolved with tapering or discontinuation of DA therapy in 8 patients available for follow-up. Only 1 of 11 patients in the series met criteria for the dopaminergic dysregulation syndrome described above, although six patients simultaneously developed other inappropriate behaviors such as hypersexuality [86]. (See 'Dopaminergic dysregulation syndrome' above.)

A randomized crossover trial of 17 patients found that amantadine (target dose 100 mg twice daily), administered as add-on to baseline antiparkinsonian medications, was effective for reducing or abolishing pathologic gambling in all treated patients [89]. However, five patients dropped out of the trial due to side effects that included confusion, orthostatic hypotension, insomnia, and visual hallucinations. The high drop-out rate is consistent with the notion that amantadine may be poorly tolerated in patients with PD taking other antiparkinsonian medications. (See 'Amantadine' below.)

Dopamine agonist withdrawal syndrome — The dopamine agonist (DA) withdrawal syndrome is described in some patients with PD who abruptly stop taking a DA [90-92]. In retrospective studies, the frequency of the syndrome among patients who withdraw from DAs ranged from 8 to 19 percent [90,91,93]. Symptoms resemble those of cocaine withdrawal and include anxiety, panic attacks, depression, sweating, nausea, pain, fatigue, dizziness, and drug craving. These symptoms were refractory to other antiparkinson medications, including levodopa, and only responded to resuming the DA.

MAO B INHIBITORS — Selegiline, a selective monoamine oxidase (MAO) type B inhibitor [94], is modestly effective as symptomatic treatment for PD [95] and may have neuroprotective properties. (See "Neuroprotective therapy for Parkinson disease", section on 'Selegiline'.)

In many individuals, selegiline monotherapy does not produce a functionally significant benefit. However, the use of selegiline in early PD is a reasonable option as long as the patient understands its limitations.

The selective MAO B inhibitor rasagiline has neuroprotective properties in animal models and appears modestly effective as symptomatic treatment for PD in human clinical trials [96,97]. (See "Neuroprotective therapy for Parkinson disease", section on 'Rasagiline'.)

Effectiveness — Evidence supporting the symptomatic effect of MAO B inhibitors for PD comes from a 2004 meta-analysis that examined data from 17 randomized trials involving 3525 patients [98]. These individual trials compared MAO B inhibitors (predominately selegiline) with either levodopa or placebo (predominately placebo) in the treatment of early PD. Many of these trials were limited by short-term follow-up, poor reporting of results, and absence of quality of life data. With these limitations in mind, the following observations were made [98]:

Data for clinical rating scales were available from six trials of selegiline; treatment with MAO B inhibitors was associated with significantly better total scores, motor scores, and activities of daily living scores on the Unified Parkinson disease rating scale (UPDRS) (table 1) at three months compared with controls.

Data on the need for levodopa were available from eight studies with a median follow-up of 13 months; treatment with MAO B inhibitors was associated with a delay in the need for additional levodopa compared with controls.

Data on motor complications were available from five trials; treatment with MAO B inhibitors was associated with a modest reduction in the development of motor fluctuations compared with controls. However, MAO B treatment was not associated with a significant difference in the incidence of dyskinesia.

Data on mortality were available from 10 trials, nine of which involved selegiline. MAO B inhibitor treatment was not associated with increased mortality compared with controls, in contrast to one observational study from the United Kingdom that showed increased mortality in patients using selegiline [99]. The results of the UK study have not been confirmed by subsequent reports, including an earlier meta-analysis [100-102].

A subsequent (2012) systematic review identified 12 randomized controlled trials comparing MAO B inhibitors (11 trials used selegiline) with placebo for the treatment of early PD in 2514 patients [103]. The findings supported a small symptomatic benefit of treatment on parkinsonian impairment and disability scores at one year.

Additional evidence supporting the long-term symptomatic benefit of selegiline for PD comes from the continuation phase of a randomized controlled trial involving 157 patients with PD, in which patients who were initially assigned to selegiline in the earlier phase of the study were treated with combined selegiline and levodopa, while those initially assigned to placebo were treated with combined placebo and levodopa [104]. At seven years, treatment with the combination of selegiline and levodopa was associated with significantly better symptom control than treatment with placebo and levodopa.

Uncertainty remains about the relative risks and benefits of MAO B inhibitors, as few trials compared them with other antiparkinson medications [98,105]. Comparative data are particularly lacking for the dopamine agonists [105].

Dosing — The dose of selegiline used in DATATOP was 5 mg twice daily, with the second dose given at noon to avoid insomnia. However, lower doses are sufficient to induce MAO B inhibition, and 5 mg once daily in the morning is currently recommended. Doses higher than 10 mg daily are of no additional benefit and may result in nonselective MAO inhibition, thereby placing the patient at risk of hypertensive crisis due to dietary interactions with tyramine-containing foods.

Rasagiline as monotherapy for PD is usually started at 1 mg daily. When used as adjunctive therapy with levodopa, rasagiline is started at 0.5 mg once daily and can be increased to 1 mg daily based upon response and tolerability.

Adverse effects — Nausea and headache are associated with the use of MAO B inhibitors, and selegiline or its amphetamine metabolites can cause insomnia [95].

Selegiline often causes confusion in older adults, thereby limiting its use in patients with late-onset disease. As previously mentioned, selegiline enhances the effect of levodopa by slowing its oxidative metabolism. Thus, it may increase levodopa-induced side effects such as dyskinesia and psychiatric toxicity (see 'Levodopa' above). However, the need for continued selegiline is questionable once patients have reached the point of requiring levodopa. In a few case reports, rasagiline use was associated with impulse control disorders [106]. (See 'Impulse control disorders' above.)

Serious adverse reactions have rarely occurred following the concomitant use of selegiline with tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs). In practice, the vast majority of patients on these combinations are able to tolerate them for years without problems. However, the Physicians' Desk Reference (PDR) warns not to use selegiline with either tricyclics or SSRIs. The possible interaction of SSRI and MAO B inhibitor treatment in patients with PD is discussed in greater detail separately. (See "Management of comorbid problems associated with Parkinson disease", section on 'Concerns with SSRI use'.)

Recommended time intervals to avoid drug interactions when switching or discontinuing antidepressants and MAO inhibitors are reviewed separately. (See "Switching antidepressant medications in adults", section on 'Switching to or from MAOIs'.)

Unlike nonselective MAO inhibitors, selegiline does not precipitate a hypertensive crisis in patients who concomitantly ingest tyramine-containing foods. (See "Clinical presentation and diagnosis of pheochromocytoma".)

ANTICHOLINERGICS — Dopamine and acetylcholine are normally in a state of electrochemical balance in the basal ganglia. In PD, dopamine depletion produces a state of cholinergic sensitivity so that cholinergic drugs exacerbate and anticholinergic drugs improve parkinsonian symptoms [107,108].

Centrally acting anticholinergic drugs such as trihexyphenidyl and benztropine have been used for many years in PD and continue to have a useful role [109]. Other anticholinergic agents such as biperiden, orphenadrine, and procyclidine produce similar effects and are more commonly used in Europe than the United States. Benztropine also may increase the effect of dopamine by inhibiting its presynaptic reuptake, but it is not known whether this contributes to its mechanism of action.

Anticholinergic drugs are most useful as monotherapy for patients with PD who are <70 years of age and have disturbing tremor but do not have significant bradykinesia or gait disturbance. They also may be useful in patients with more advanced disease who have persistent tremor despite treatment with levodopa or dopamine agonists.

Dosing — Trihexyphenidyl is the most widely prescribed anticholinergic agent, although there is little evidence to suggest that one drug in this class is superior to another. The starting dose of trihexyphenidyl is 0.5 to 1 mg twice daily, with a gradual increase to 2 mg three times daily. Benztropine traditionally is more commonly used by psychiatrists for the management of antipsychotic drug-induced parkinsonism; the usual dose is 0.5 to 2 mg twice daily.

Adverse effects — Adverse effects of anticholinergic drugs are common and often limit their use. Older adults and cognitively impaired patients are particularly susceptible to memory impairment, confusion, and hallucinations and should not receive these drugs. When an anticholinergic drug is used to treat sialorrhea or urinary frequency, peripherally acting agents such as propantheline should be used, although confusion and hallucinations are not infrequent adverse effects with these drugs as well. Younger patients usually tolerate these agents better than older adults, although some experience dysphoric symptoms, sedation, or memory impairment.

Peripheral antimuscarinic side effects include dry mouth, blurred vision, constipation, nausea, urinary retention, impaired sweating, and tachycardia. Caution is advised in patients with known prostatic hypertrophy or closed-angle glaucoma. Discontinuation of anticholinergic drugs should be performed gradually to avoid withdrawal symptoms that may manifest as an acute exacerbation of parkinsonism, even in those in whom the clinical response has not seemed significant.

AMANTADINE — Amantadine is an antiviral agent that has mild antiparkinsonian activity [110]. Its mechanism of action is uncertain; it is known to increase dopamine release, inhibit dopamine reuptake, stimulate dopamine receptors, and it may possibly exert central anticholinergic effects [111]. Amantadine has N-methyl-D-aspartate (NMDA) receptor antagonist properties that may account for its therapeutic effect by interfering with excessive glutamate neurotransmission in the basal ganglia.

In early uncontrolled clinical trials, two-thirds of patients receiving amantadine monotherapy showed an improvement in bradykinesia, rigidity, and tremor [110]. Subsequent controlled studies demonstrated that it was more effective than anticholinergic drugs for bradykinesia and rigidity [112]. The benefit induced by amantadine appears to be transient in some patients; it is best used as short-term monotherapy in those with mild disease. Amantadine is of little benefit when added to levodopa, although the addition of levodopa to amantadine causes significant additive improvement [113].

Amantadine in divided doses of 200 to 400 mg a day may reduce the intensity of levodopa-induced dyskinesia and motor fluctuations in patients with PD. Although the published randomized trials on amantadine in advanced PD are limited by serious methodological flaws and small numbers of patients [114], experience has shown that individual patients with advanced PD who have motor fluctuations and dyskinesia can benefit dramatically, at least for a while, from the addition of amantadine to a regimen of levodopa. Furthermore, a randomized controlled trial of 56 patients with PD and levodopa-induced dyskinesia found that withdrawal compared with continuation of amantadine led to significant worsening of dyskinesia [115]. (See "Motor fluctuations and dyskinesia in Parkinson disease", section on 'Amantadine'.)

Dosing — The dose of amantadine in early PD is 200 to 300 mg daily; there is no evidence that larger doses are of additional benefit. The main advantage of this agent is a low incidence of side effects. It is excreted unchanged in the urine and should be used with caution in the presence of renal failure.

Adverse effects — Peripheral side effects include livedo reticularis and ankle edema, which are rarely severe enough to limit treatment. Confusion, hallucinations, and nightmares occur infrequently, but unpredictably, even after long periods of use without side effects. These effects are more likely when amantadine is used together with other antiparkinsonian drugs in older patients.

COMT INHIBITORS — The catechol-O-methyl transferase (COMT) inhibitors tolcapone and entacapone are ineffective when given alone, but they may prolong and potentiate the levodopa effect when given with a dose of levodopa, and thus are useful as levodopa extenders [116,117]. Inhibition of COMT reduces the peripheral (entacapone) and central (tolcapone) methylation of levodopa and dopamine, which in turn increases the plasma half-life of levodopa, produces more stable plasma levodopa concentrations, and prolongs the therapeutic effect of each dose. These medications are mainly used to treat patients with motor fluctuations who are experiencing end-of-dose wearing "off" periods, as discussed separately. (See "Motor fluctuations and dyskinesia in Parkinson disease" and "Motor fluctuations and dyskinesia in Parkinson disease", section on '"Wearing off" phenomenon'.)

There appears to be no advantage for using levodopa combined with a COMT inhibitor, compared with levodopa alone, as initial therapy for PD, or as add-on therapy for levodopa-treated patients without motor complications.

The STRIDE-PD trial randomly assigned 747 patients with early PD to levodopa/carbidopa alone or combined with entacapone [118]. Patients assigned to combined therapy with entacapone had a shorter time to onset of dyskinesia and increased frequency of dyskinesia.

In a trial of 750 levodopa-treated patients without motor fluctuations, adjunct entacapone did not improve UPDRS (table 1) motor scores [119].

Dosing — The starting dose of tolcapone is 100 mg three times daily; the clinical effect is evident immediately. The dose of entacapone is one 200 mg tablet with each dose of levodopa, up to a maximum of eight doses per day.

Adverse effects — The most common side effects of tolcapone are due to increased dopaminergic stimulation and include dyskinesia, hallucinations, confusion, nausea, and orthostatic hypotension. The adverse effects are managed by lowering the dose of levodopa either before or after the addition of tolcapone. Diarrhea that is poorly responsive to antidiarrheal medications appears in approximately 5 percent of patients. An orange discoloration of the urine is a common but benign adverse event. Elevations in liver enzymes may rarely occur.

Side effects of entacapone are similar to tolcapone, although entacapone has thus far not been associated with hepatotoxicity.

Tolcapone was removed from the market in Europe and Canada in 1998 after three reported deaths from hepatotoxicity in patients using tolcapone. The drug remained available in the United States with the recommendation that it be used for treatment of motor fluctuations only after other methods have been exhausted and with regular monitoring of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Tolcapone was reintroduced in Europe in 2006 with accumulating data suggesting that it has a negligible risk of severe or life-threatening hepatotoxicity when used appropriately with liver function monitoring [120-122]. Its continued use in the United States has also been associated with a very low risk of hepatotoxicity when appropriately monitored with liver function tests for a period of six months after starting the drug.

ESTROGEN — Low-dose estrogen may be helpful as adjunctive therapy in postmenopausal women with motor fluctuations on antiparkinsonian medication [123,124]. In one study, administration of oral conjugated estrogen 0.625 mg daily for eight weeks significantly improved "on" time and motor control in such women, although it did not result in global improvement on a scale rating activities of daily living [123]. There is no evidence that estrogen has a specific effect on dopamine receptors; the benefit attributable to estrogen use may be related to an overall sense of well-being.

It is not clear if these results would be similar in women taking combined estrogen/progestin therapy (necessary in women with an intact uterus). Furthermore, concerns about adverse effects associated with long-term estrogen/progestin therapy may limit its use in PD. (See "Menopausal hormone therapy: Benefits and risks".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info" and the keyword(s) of interest.)

Basics topics (see "Patient information: Parkinson disease (The Basics)" and "Patient information: Medicines for Parkinson disease (The Basics)")

Beyond the Basics topics (see "Patient information: Parkinson disease treatment options — medications (Beyond the Basics)")


Either levodopa or a dopamine agonist can be used initially for patients who require symptomatic therapy for Parkinson disease (PD). It is reasonable to initiate therapy with a dopamine agonist in younger patients (age <65 years), and with levodopa in older patients (age >65 years). However, there are exceptions to these general rules, and all treatments should be individualized. Levodopa is the drug of choice if symptoms, particularly those related to bradykinesia, seriously threaten the patient's lifestyle. Practitioners should always try to find the lowest but still effective dose of dopaminergic medication, either singly or in combination, for patients with PD, each of whom must be evaluated and managed in a highly individual way. (See 'Symptomatic therapy' above.)

Levodopa (combined with a peripheral decarboxylase inhibitor, ie, Sinemet, Madopar, or Prolopa) is the most effective symptomatic therapy for PD and should be introduced when the patient and physician jointly decide that quality of life, particularly related to job performance or self care, is substantially compromised. However, levodopa is associated with a higher risk of dyskinesia than the dopamine agonists. There does not appear to be a benefit of initiating treatment with controlled release levodopa compared with the immediate release preparation, and the former may limit the ability to follow the initial response to therapy. As a result, it is recommended that therapy be initiated with an immediate release preparation with a subsequent switch to controlled release if indicated. (See 'Levodopa' above.)

With the exception of pergolide and cabergoline, the dopamine agonists are a useful group of drugs that may be employed either as monotherapy in early PD or in combination with other antiparkinsonian drugs for treatment of more advanced disease. They are ineffective in patients who show no response to levodopa. They possibly delay the need to initiate levodopa therapy and the subsequent appearance of levodopa dyskinesia and motor fluctuations, but at the risk of slightly less efficacy and increased adverse effects. (See 'Dopamine agonists' above.)

Selegiline has mild symptomatic benefit, and it may be used in patients with early PD. Its use should be limited to patients with early disease since the symptomatic benefits are unlikely to be significant in those with more advanced PD. Nevertheless, patients should understand that there may not be much symptomatic improvement if selegiline is the initial treatment for early PD, and early follow-up and consideration of additional symptomatic therapy should be arranged. The value of selegiline for neuroprotection is unclear. (See 'MAO B inhibitors' above.)

Rasagiline is a monoamine oxidase (MAO) B inhibitor that has been demonstrated in randomized trials to produce a statistically significant benefit as monotherapy in PD. However, it is uncertain whether it also produces a clinically meaningful benefit that is evident to the patient. (See 'MAO B inhibitors' above.)

Anticholinergic drugs should be reserved for younger patients in whom tremor is the predominant problem. Their use in older or demented individuals and those without tremor is strongly discouraged. Amantadine is a relatively weak antiparkinsonian drug with low toxicity that is most useful in treating patients with early or mild PD and perhaps later when dyskinesia becomes problematic. (See 'Anticholinergics' above and 'Amantadine' above.)

Use of UpToDate is subject to the Subscription and License Agreement.


  1. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines. Neurology 2001; 56:S1.
  2. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA 2014; 311:1670.
  3. Miyasaki JM, Martin W, Suchowersky O, et al. Practice parameter: initiation of treatment for Parkinson's disease: an evidence-based review: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2002; 58:11.
  4. Stagg P, Grice T. Nasogastric medication for perioperative Parkinson's rigidity during anaesthesia emergence. Anaesth Intensive Care 2011; 39:1128.
  5. Factor SA. Fatal Parkinsonism-hyperpyrexia syndrome in a Parkinson's disease patient while actively treated with deep brain stimulation. Mov Disord 2007; 22:148.
  6. Newman EJ, Grosset DG, Kennedy PG. The parkinsonism-hyperpyrexia syndrome. Neurocrit Care 2009; 10:136.
  7. Ferreira JJ, Katzenschlager R, Bloem BR, et al. Summary of the recommendations of the EFNS/MDS-ES review on therapeutic management of Parkinson's disease. Eur J Neurol 2013; 20:5.
  8. Parcopa: a rapidly dissolving formulation of carbidopa/levodopa. Med Lett Drugs Ther 2005; 47:12.
  9. Ondo WG, Shinawi L, Moore S. Comparison of orally dissolving carbidopa/levodopa (Parcopa) to conventional oral carbidopa/levodopa: A single-dose, double-blind, double-dummy, placebo-controlled, crossover trial. Mov Disord 2010; 25:2724.
  10. Koller WC, Hutton JT, Tolosa E, Capilldeo R. Immediate-release and controlled-release carbidopa/levodopa in PD: a 5-year randomized multicenter study. Carbidopa/Levodopa Study Group. Neurology 1999; 53:1012.
  11. Miller JW, Selhub J, Nadeau MR, et al. Effect of L-dopa on plasma homocysteine in PD patients: relationship to B-vitamin status. Neurology 2003; 60:1125.
  12. Rogers JD, Sanchez-Saffon A, Frol AB, Diaz-Arrastia R. Elevated plasma homocysteine levels in patients treated with levodopa: association with vascular disease. Arch Neurol 2003; 60:59.
  13. O'Suilleabhain PE, Bottiglieri T, Dewey RB Jr, et al. Modest increase in plasma homocysteine follows levodopa initiation in Parkinson's disease. Mov Disord 2004; 19:1403.
  14. Postuma RB, Lang AE. Homocysteine and levodopa: should Parkinson disease patients receive preventative therapy? Neurology 2004; 63:886.
  15. Toth C, Brown MS, Furtado S, et al. Neuropathy as a potential complication of levodopa use in Parkinson's disease. Mov Disord 2008; 23:1850.
  16. Toth C, Breithaupt K, Ge S, et al. Levodopa, methylmalonic acid, and neuropathy in idiopathic Parkinson disease. Ann Neurol 2010; 68:28.
  17. Ceravolo R, Cossu G, Bandettini di Poggio M, et al. Neuropathy and levodopa in Parkinson's disease: evidence from a multicenter study. Mov Disord 2013; 28:1391.
  18. Uncini A, Eleopra R, Onofrj M. Polyneuropathy associated with duodenal infusion of levodopa in Parkinson's disease: features, pathogenesis and management. J Neurol Neurosurg Psychiatry 2015; 86:490.
  19. Calabresi P, Di Filippo M, Ghiglieri V, et al. Levodopa-induced dyskinesias in patients with Parkinson's disease: filling the bench-to-bedside gap. Lancet Neurol 2010; 9:1106.
  20. Aquino CC, Fox SH. Clinical spectrum of levodopa-induced complications. Mov Disord 2015; 30:80.
  21. Impact of deprenyl and tocopherol treatment on Parkinson's disease in DATATOP patients requiring levodopa. Parkinson Study Group. Ann Neurol 1996; 39:37.
  22. Block G, Liss C, Reines S, et al. Comparison of immediate-release and controlled release carbidopa/levodopa in Parkinson's disease. A multicenter 5-year study. The CR First Study Group. Eur Neurol 1997; 37:23.
  23. Quinn N, Critchley P, Marsden CD. Young onset Parkinson's disease. Mov Disord 1987; 2:73.
  24. Kumar N, Van Gerpen JA, Bower JH, Ahlskog JE. Levodopa-dyskinesia incidence by age of Parkinson's disease onset. Mov Disord 2005; 20:342.
  25. Warren Olanow C, 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.
  26. Hauser RA, McDermott MP, Messing S. Factors associated with the development of motor fluctuations and dyskinesias in Parkinson disease. Arch Neurol 2006; 63:1756.
  27. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group. JAMA 2000; 284:1931.
  28. Holloway RG, Shoulson I, Fahn S, et al. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 2004; 61:1044.
  29. PD Med Collaborative Group, Gray R, Ives N, et al. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet 2014; 384:1196.
  30. Katzenschlager R, Head J, Schrag A, et al. Fourteen-year final report of the randomized PDRG-UK trial comparing three initial treatments in PD. Neurology 2008; 71:474.
  31. Parkinson Study Group CALM Cohort Investigators. Long-term effect of initiating pramipexole vs levodopa in early Parkinson disease. Arch Neurol 2009; 66:563.
  32. Fahn S, Bressman SB. Should levodopa therapy for Parkinsonism be started early or late? Evidence against early treatment. Can J Neurol Sci 1984; 11:200.
  33. Melamed E. Initiation of levodopa therapy in parkinsonian patients should be delayed until the advanced stages of the disease. Arch Neurol 1986; 43:402.
  34. Markham CH, Diamond SG. Modification of Parkinson's disease by long-term levodopa treatment. Arch Neurol 1986; 43:405.
  35. Olanow CW, Agid Y, Mizuno Y, et al. Levodopa in the treatment of Parkinson's disease: current controversies. Mov Disord 2004; 19:997.
  36. Tanaka M, Sotomatsu A, Kanai H, Hirai S. Dopa and dopamine cause cultured neuronal death in the presence of iron. J Neurol Sci 1991; 101:198.
  37. Rajput AH. The protective role of levodopa in the human substantia nigra. Adv Neurol 2001; 86:327.
  38. Parkkinen L, O'Sullivan SS, Kuoppamäki M, et al. Does levodopa accelerate the pathologic process in Parkinson disease brain? Neurology 2011; 77:1420.
  39. Blunt SB, Jenner P, Marsden CD. Suppressive effect of L-dopa on dopamine cells remaining in the ventral tegmental area of rats previously exposed to the neurotoxin 6-hydroxydopamine. Mov Disord 1993; 8:129.
  40. Dziewczapolski G, Murer G, Agid Y, et al. Absence of neurotoxicity of chronic L-DOPA in 6-hydroxydopamine-lesioned rats. Neuroreport 1997; 8:975.
  41. Murer MG, Dziewczapolski G, Menalled LB, et al. Chronic levodopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions. Ann Neurol 1998; 43:561.
  42. Agid Y, Chase T, Marsden D. Adverse reactions to levodopa: drug toxicity or progression of disease? Lancet 1998; 351:851.
  43. Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson's disease. N Engl J Med 2004; 351:2498.
  44. Olanow CW, Obeso JA. Levodopa toxicity and Parkinson disease: still a need for equipoise. Neurology 2011; 77:1416.
  45. LeWitt PA, Dubow J, Singer C. Is levodopa toxic? Insights from a brain bank. Neurology 2011; 77:1414.
  46. Olanow CW. Levodopa: effect on cell death and the natural history of Parkinson's disease. Mov Disord 2015; 30:37.
  47. Deleu D, Hanssens Y, Northway MG. Subcutaneous apomorphine : an evidence-based review of its use in Parkinson's disease. Drugs Aging 2004; 21:687.
  48. Fahn S. Is levodopa toxic? Neurology 1996; 47:S184.
  49. International symposium on early dopamine agonist therapy of Parkinson's disease. Arch Neurol 1988; 45:204.
  50. Marras C, Lang A. Invited article: changing concepts in Parkinson disease: moving beyond the decade of the brain. Neurology 2008; 70:1996.
  51. Hubble JP, Koller WC, Cutler NR, et al. Pramipexole in patients with early Parkinson's disease. Clin Neuropharmacol 1995; 18:338.
  52. 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.
  53. Barone P, Bravi D, Bermejo-Pareja F, et al. Pergolide monotherapy in the treatment of early PD: a randomized, controlled study. Pergolide Monotherapy Study Group. Neurology 1999; 53:573.
  54. Korczyn AD, Brunt ER, Larsen JP, et al. A 3-year randomized trial of ropinirole and bromocriptine in early Parkinson's disease. The 053 Study Group. Neurology 1999; 53:364.
  55. Watts RL, Jankovic J, Waters C, et al. Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology 2007; 68:272.
  56. 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. N Engl J Med 2000; 342:1484.
  57. Poewe W, Rascol O, Barone P, et al. Extended-release pramipexole in early Parkinson disease: a 33-week randomized controlled trial. Neurology 2011; 77:759.
  58. Stowe RL, Ives NJ, Clarke C, et al. Dopamine agonist therapy in early Parkinson's disease. Cochrane Database Syst Rev 2008; :CD006564.
  59. LeWitt PA, Ward CD, Larsen TA, et al. Comparison of pergolide and bromocriptine therapy in parkinsonism. Neurology 1983; 33:1009.
  60. Guttman M. Double-blind comparison of pramipexole and bromocriptine treatment with placebo in advanced Parkinson's disease. International Pramipexole-Bromocriptine Study Group. Neurology 1997; 49:1060.
  61. Pezzoli G, Martignoni E, Pacchetti C, et al. Pergolide compared with bromocriptine in Parkinson's disease: a multicenter, crossover, controlled study. Mov Disord 1994; 9:431.
  62. Korczyn AD, Brooks DJ, Brunt ER, et al. Ropinirole versus bromocriptine in the treatment of early Parkinson's disease: a 6-month interim report of a 3-year study. 053 Study Group. Mov Disord 1998; 13:46.
  63. Apomorphine (Apokyn) for advanced Parkinson's Disease. Med Lett Drugs Ther 2005; 47:7.
  64. Schilling JC, Adamus WS, Palluk R. Neuroendocrine and side effect profile of pramipexole, a new dopamine receptor agonist, in humans. Clin Pharmacol Ther 1992; 51:541.
  65. Frucht S, Rogers JD, Greene PE, et al. Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology 1999; 52:1908.
  66. Pritchett AM, Morrison JF, Edwards WD, et al. Valvular heart disease in patients taking pergolide. Mayo Clin Proc 2002; 77:1280.
  67. Van Camp G, Flamez A, Cosyns B, et al. Treatment of Parkinson's disease with pergolide and relation to restrictive valvular heart disease. Lancet 2004; 363:1179.
  68. Baseman DG, O'Suilleabhain PE, Reimold SC, et al. Pergolide use in Parkinson disease is associated with cardiac valve regurgitation. Neurology 2004; 63:301.
  69. Schade R, Andersohn F, Suissa S, et al. Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med 2007; 356:29.
  70. Zanettini R, Antonini A, Gatto G, et al. Valvular heart disease and the use of dopamine agonists for Parkinson's disease. N Engl J Med 2007; 356:39.
  71. Antonini A, Poewe W. Fibrotic heart-valve reactions to dopamine-agonist treatment in Parkinson's disease. Lancet Neurol 2007; 6:826.
  72. Corvol JC, Anzouan-Kacou JB, Fauveau E, et al. Heart valve regurgitation, pergolide use, and parkinson disease: an observational study and meta-analysis. Arch Neurol 2007; 64:1721.
  73. Roth BL. Drugs and valvular heart disease. N Engl J Med 2007; 356:6.
  74. FDA announces voluntary withdrawal of pergolide products. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108877.htm (Accessed on October 27, 2010).
  75. Giovannoni G, O'Sullivan JD, Turner K, et al. Hedonistic homeostatic dysregulation in patients with Parkinson's disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry 2000; 68:423.
  76. Lawrence AD, Evans AH, Lees AJ. Compulsive use of dopamine replacement therapy in Parkinson's disease: reward systems gone awry? Lancet Neurol 2003; 2:595.
  77. Evans AH, Katzenschlager R, Paviour D, et al. Punding in Parkinson's disease: its relation to the dopamine dysregulation syndrome. Mov Disord 2004; 19:397.
  78. Pezzella FR, Colosimo C, Vanacore N, et al. Prevalence and clinical features of hedonistic homeostatic dysregulation in Parkinson's disease. Mov Disord 2005; 20:77.
  79. Evans AH, Lawrence AD, Potts J, et al. Factors influencing susceptibility to compulsive dopaminergic drug use in Parkinson disease. Neurology 2005; 65:1570.
  80. Voon V, Fox SH. Medication-related impulse control and repetitive behaviors in Parkinson disease. Arch Neurol 2007; 64:1089.
  81. 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.
  82. Moore TJ, Glenmullen J, Mattison DR. Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs. JAMA Intern Med 2014; 174:1930.
  83. Voon V, Hassan K, Zurowski M, et al. Prevalence of repetitive and reward-seeking behaviors in Parkinson disease. Neurology 2006; 67:1254.
  84. Voon V, Hassan K, Zurowski M, et al. Prospective prevalence of pathologic gambling and medication association in Parkinson disease. Neurology 2006; 66:1750.
  85. Driver-Dunckley E, Samanta J, Stacy M. Pathological gambling associated with dopamine agonist therapy in Parkinson's disease. Neurology 2003; 61:422.
  86. Dodd ML, Klos KJ, Bower JH, et al. Pathological gambling caused by drugs used to treat Parkinson disease. Arch Neurol 2005; 62:1377.
  87. Weintraub D, Siderowf AD, Potenza MN, et al. Association of dopamine agonist use with impulse control disorders in Parkinson disease. Arch Neurol 2006; 63:969.
  88. Weintraub D, Papay K, Siderowf A, Parkinson's Progression Markers Initiative. Screening for impulse control symptoms in patients with de novo Parkinson disease: a case-control study. Neurology 2013; 80:176.
  89. Thomas A, Bonanni L, Gambi F, et al. Pathological gambling in Parkinson disease is reduced by amantadine. Ann Neurol 2010; 68:400.
  90. Rabinak CA, Nirenberg MJ. Dopamine agonist withdrawal syndrome in Parkinson disease. Arch Neurol 2010; 67:58.
  91. Pondal M, Marras C, Miyasaki J, et al. Clinical features of dopamine agonist withdrawal syndrome in a movement disorders clinic. J Neurol Neurosurg Psychiatry 2013; 84:130.
  92. Nirenberg MJ. Dopamine agonist withdrawal syndrome: implications for patient care. Drugs Aging 2013; 30:587.
  93. Limotai N, Oyama G, Go C, et al. Addiction-like manifestations and Parkinson's disease: a large single center 9-year experience. Int J Neurosci 2012; 122:145.
  94. Olanow CW. Selegiline: current perspectives on issues related to neuroprotection and mortality. Neurology 1996; 47:S210.
  95. Horn S, Stern MB. The comparative effects of medical therapies for Parkinson's disease. Neurology 2004; 63:S7.
  96. Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol 2002; 59:1937.
  97. Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004; 61:561.
  98. Ives NJ, Stowe RL, Marro J, et al. Monoamine oxidase type B inhibitors in early Parkinson's disease: meta-analysis of 17 randomised trials involving 3525 patients. BMJ 2004; 329:593.
  99. Thorogood M, Armstrong B, Nichols T, Hollowell J. Mortality in people taking selegiline: observational study. BMJ 1998; 317:252.
  100. Olanow CW, Myllylä VV, Sotaniemi KA, et al. Effect of selegiline on mortality in patients with Parkinson's disease: a meta-analysis. Neurology 1998; 51:825.
  101. Donnan PT, Steinke DT, Stubbings C, et al. Selegiline and mortality in subjects with Parkinson's disease: a longitudinal community study. Neurology 2000; 55:1785.
  102. Marras C, McDermott MP, Rochon PA, et al. Survival in Parkinson disease: thirteen-year follow-up of the DATATOP cohort. Neurology 2005; 64:87.
  103. Turnbull K, Caslake R, Macleod A, et al. Monoamine oxidase B inhibitors for early Parkinson's disease. Cochrane Database Syst Rev 2012; 3:CD004898.
  104. Pålhagen S, Heinonen E, Hägglund J, et al. Selegiline slows the progression of the symptoms of Parkinson disease. Neurology 2006; 66:1200.
  105. Caslake R, Macleod A, Ives N, et al. Monoamine oxidase B inhibitors versus other dopaminergic agents in early Parkinson's disease. Cochrane Database Syst Rev 2009; :CD006661.
  106. Vitale C, Santangelo G, Erro R, et al. Impulse control disorders induced by rasagiline as adjunctive therapy for Parkinson's disease: report of 2 cases. Parkinsonism Relat Disord 2013; 19:483.
  107. Duvoisin RC. Cholinergic-anticholinergic antagonism in parkinsonism. Arch Neurol 1967; 17:124.
  108. Katzenschlager R, Sampaio C, Costa J, Lees A. Anticholinergics for symptomatic management of Parkinson's disease. Cochrane Database Syst Rev 2003; :CD003735.
  109. Lang AE. Treatment of Parkinson's disease with agents other than levodopa and dopamine agonists: controversies and new approaches. Can J Neurol Sci 1984; 11:210.
  110. Schwab RS, Poskanzer DC, England AC Jr, Young RR. Amantadine in Parkinson's disease. Review of more than two years' experience. JAMA 1972; 222:792.
  111. Amantadine and other antiglutamate agents: management of Parkinson's disease. Mov Disord 2002; 17 Suppl 4:S13.
  112. Parkes JD, Baxter RC, Marsden CD, Rees JE. Comparative trial of benzhexol, amantadine, and levodopa in the treatment of Parkinson's disease. J Neurol Neurosurg Psychiatry 1974; 37:422.
  113. Godwin-Austen RB, Frears CC, Bergmann S, et al. Combined treatment of parkinsonism with L-dopa and amantadine. Lancet 1970; 2:383.
  114. Crosby NJ, Deane KH, Clarke CE. Amantadine for dyskinesia in Parkinson's disease. Cochrane Database Syst Rev 2003; :CD003467.
  115. Ory-Magne F, Corvol JC, Azulay JP, et al. Withdrawing amantadine in dyskinetic patients with Parkinson disease: the AMANDYSK trial. Neurology 2014; 82:300.
  116. Nutt JG. Catechol-O-methyltransferase inhibitors for treatment of Parkinson's disease. Lancet 1998; 351:1221.
  117. Brooks DJ, Sagar H, UK-Irish Entacapone Study Group. Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinson's disease: a randomised, placebo controlled, double blind, six month study. J Neurol Neurosurg Psychiatry 2003; 74:1071.
  118. 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.
  119. Olanow CW, Kieburtz K, Stern M, et al. Double-blind, placebo-controlled study of entacapone in levodopa-treated patients with stable Parkinson disease. Arch Neurol 2004; 61:1563.
  120. Olanow CW. Tolcapone and hepatotoxic effects. Tasmar Advisory Panel. Arch Neurol 2000; 57:263.
  121. Borges N. Tolcapone in Parkinson's disease: liver toxicity and clinical efficacy. Expert Opin Drug Saf 2005; 4:69.
  122. Lees AJ, Ratziu V, Tolosa E, Oertel WH. Safety and tolerability of adjunctive tolcapone treatment in patients with early Parkinson's disease. J Neurol Neurosurg Psychiatry 2007; 78:944.
  123. Tsang KL, Ho SL, Lo SK. Estrogen improves motor disability in parkinsonian postmenopausal women with motor fluctuations. Neurology 2000; 54:2292.
  124. Saunders-Pullman R, Gordon-Elliott J, Parides M, et al. The effect of estrogen replacement on early Parkinson's disease. Neurology 1999; 52:1417.
Topic 4896 Version 27.0

Topic Outline



All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.