A previously healthy 65-year-old man presents with a tremor of his right hand. The examination reveals a resting tremor, cogwheel rigidity, and a shuffling gait. He is diagnosed with early Parkinson disease, and he and his wife inquire about drug therapy.
What are the risks and benefits of dopamine agonists in place of or in addition to levodopa for patients with early Parkinson disease?
Dopamine agonists, such as pramipexole (Mirapex), ropinirole (Requip), pergolide (formerly Permax), and apomorphine (Apokyn), improve the motor fluctuations and dyskinesias that commonly occur with levodopa, but at the expense of increasing nonmotor adverse effects and noncompliance. An individual, case-based approach should be employed.1
Approximately one in 300 persons in the United States has Parkinson disease.2 Risk factors include older age and genetic predisposition. As the population ages, the prevalence of Parkinson disease in the United States is estimated to double in the next couple of decades.2 Unlike Alzheimer disease and Lewy body dementia, early Parkinson disease is characterized by motor symptoms with preservation of cognitive function. The core features of Parkinson disease are resting tremor, bradykinesia, rigidity, and postural instability.2 A video clip of these features can be found at http://content.nejm.org/cgi/content/full/353/10/1021/DC1.
Traditional pharmacotherapy reduces disability and helps maintain quality of life. Levodopa is the most effective treatment for control of symptoms, but loses effectiveness over time and eventually results in motor fluctuations and dyskinesias. According to the American Academy of Neurology, dopamine agonists can be used as an alternative initial therapy and as an adjunct to levodopa to decrease long-term motor complications.3 This approach is especially desirable in younger patients with mild disease to delay the use of levodopa. However, all patients with Parkinson disease will likely need levodopa at some point.
This Cochrane review is the first meta-analysis to investigate the risks and benefits of dopamine agonists as a class in the treatment of early Parkinson disease.1 It concluded that the use of a dopamine agonist had no bearing on mortality rates. Additionally, combination therapy with levodopa and dopamine agonists lowered the required dose of levodopa. However, comparison of symptom control among groups was limited by poor quantitative data reporting. In general, dopamine agonists were inferior to levodopa monotherapy for symptomatic control of the cardinal motor symptoms of Parkinson disease. Although participants taking dopamine agonists reported less motor fluctuation and dyskinesia, nonmotor side effects were more common.
Edema was more common in patients treated with dopamine agonists, followed by hallucinations, constipation, somnolence, dizziness, and nausea. Patients using dopamine agonists as monotherapy or as an adjunct to levodopa were twice as likely to withdraw from studies because of side effects compared with levodopa monotherapy or placebo. Comparing the effects of different dopamine agonists was limited by confounding variables. Nevertheless, significant increases in somnolence and hallucination occurred in patients taking ergot-derived dopamine agonists, such as bromocriptine (Parlodel; seldom used in the United States) and pergolide, compared with nonergot derivatives.1
Background: Dopamine agonists are being used increasingly as first-line treatment for Parkinson disease, but uncertainty remains about their clinical- and cost-effectiveness relative to levodopa.
Objectives: This meta-analysis aims to quantify more reliably the benefits and risks of dopamine agonists compared with placebo or levodopa in early Parkinson disease.
Search Strategy: The search sources included CENTRAL (The Cochrane Library), Medline, EMBASE, PubMed, LILACS, and Web of Science, plus major journalism in the field, abstract books, conference proceedings, and reference lists of retrieved publications.
Selection Criteria: Randomized trials comparing an orally administered dopamine agonist (with or without levodopa) versus placebo or levodopa or both placebo and levodopa in participants with early Parkinson disease.
Data Collection and Analysis: Two authors independently extracted data on physician-rated disability, motor complications, other adverse effects, treatment concordance, levodopa dose, and mortality.
Main Results: Identified were 29 eligible trials involving 5,247 participants. Participants randomized to a dopamine agonist were less likely to develop dyskinesia (odds ratio [OR] = 0.51; 95% confidence interval [CI], 0.43 to 0.59; P < .00001), dystonia (OR = 0.64; 95% CI, 0.51 to 0.81; P = .0002), and motor fluctuations (OR = 0.75; 95% CI, 0.63 to 0.90; P = .002) than participants treated with levodopa. However, various nonmotor adverse effects, including edema (OR = 3.68; 95% CI, 2.62 to 5.18; P < .00001), somnolence (OR = 1.49; 95% CI, 1.12 to 2.00; P = .007), constipation (OR = 1.59; 95% CI, 1.11 to 2.28; P = .01), dizziness (OR = 1.45; 95% CI, 1.09 to 1.92; P = .01), hallucinations (OR = 1.69; 95% CI, 1.13 to 2.52; P = .01), and nausea (OR = 1.32; 95% CI, 1.05 to 1.66; P = .02) were all increased in agonist-treated participants (compared with levodopa-treated participants). Participants treated with agonists were also significantly more likely to discontinue treatment because of adverse events (OR = 2.49; 95% CI, 2.08 to 2.98; P < .00001). Symptomatic control of Parkinson disease was better with levodopa than with agonists, but data were reported too inconsistently and incompletely to meta-analyze.
Authors' Conclusions: This meta-analysis confirms that motor complications are reduced with dopamine agonists compared with levodopa, but also establishes that other important adverse effects are increased and symptom control is poorer with agonists. Larger, long-term comparative trials assessing patient-rated quality of life are needed to assess more reliably the balance of benefits and risks of dopamine agonists compared with levodopa.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org).
The authors of this Cochrane review drew their conclusions by analyzing 29 trials that compared dopamine agonists (with or without levodopa) versus levodopa alone, or dopamine agonists versus placebo.1 However, these studies varied greatly in the number of participants, method of randomization, concealment of allocation, length of follow-up, and method of data analysis. Nine of the trials were not double-blinded, and 21 of the trials used an ergot-derived dopamine agonist (e.g., bromocriptine). Given the heterogeneity among trials, further research with dopamine agonists is needed to address cost-effectiveness, psychiatric outcomes, neuroprotective effects, and health-related quality of life measures.
Levodopa remains the mainstay of Parkinson disease therapy and requires careful dosage titration for adequate clinical benefit.4 In early disease, physicians can optimize therapy with other medications, such as monoamine oxidase B (MAOB) inhibitors (e.g., selegiline [Eldepryl], rasagiline [Azilect]), anticholinergics, N-methyl-d-aspartate antagonists (e.g., amantadine [Symmetrel]), and dopamine agonists.2,4 Pramipexole and ropinirole are the most commonly prescribed nonergot dopamine agonists in the United States. Levodopa remains best tolerated as first-line therapy in older patients with dementia who are prone to excessive sleepiness or orthostatic hypotension.1 High-protein meals may compete with levodopa absorption in the gut and at the blood-brain barrier. Scheduled doses of levodopa between meals optimizes absorption.4 Deep brain stimulation is an effective treatment for patients with refractory motor symptoms, but it carries a significant risk of adverse events.5 Exercise, physical therapy, nutrition, safety prevention, and speech therapy may help maintain physical and emotional well-being in patients with Parkinson disease.2
No medications have convincingly been shown to confer neuroprotection for Parkinson disease. Longitudinal neuroimaging studies with dopamine agonists ropinirole or pramipexole versus levodopa showed a decreased rate of dopaminergic loss in the dopamine agonist groups.6,7 The recent Attenuation of Disease progression with Agilect/Azilect once daily study, which looked at early versus delayed initiation of the MAOB inhibitor rasagiline, suggests that early treatment with 1 mg per day of rasagiline may slow the progression of Parkinson disease.8
Treatment of Parkinson disease is within the scope of a family physician, but requires frequent office visits and medication titration. The Movement Disorder Society recently revised the Unified Parkinson's Disease Rating Scale (available at http://www.movementdisorders.org/publications/rating_scales/mds_updrs.pdf), which is used to track disease progression, treatment response, and complications.9 The Parkinson's Disease Foundation (http://www.pdf.org) provides resources for patients and their families.