Practice parameter: Initiation of treatment for Parkinson’s disease: An evidence-based review

In 1993, the last AAN Practice Parameter on medical treatment of Parkinson’s disease (PD) concluded that levodopa was the most effective drug for management of this disorder. Since then, a number of new compounds including non-ergot dopamine agonists (DA) and sustained-release levodopa have been released and studied. Thus, the issue of treatment in de novo PD patients warrants reexamination. Specific questions include: 1) does selegiline offer neuroprotection; 2) what is the best agent with which to initiate symptomatic treatment in de novo PD; and 3) is there a benefit of sustained release levodopa over immediate-release levodopa? Using evidence-based principles, a literature review using MEDLINE, EMBASE, and the Cochrane Library was performed to identify all human trials in de novo PD between 1966 and 1999. Only articles that fulfilled class I or class II evidence were included. Based on this review, the authors conclude: 1) Selegiline has very mild symptomatic benefit (level A, class II evidence) with no evidence for neuroprotective benefit (level U, class II evidence). 2) For PD patients requiring initiation of symptomatic therapy, either levodopa or a DA can be used (level A, class I and class II evidence). Levodopa provides superior motor benefit but is associated with a higher risk of dyskinesia. 3) No evidence was found that initiating treatment with sustained-release levodopa provides an advantage over immediate-release levodopa (level B, class II evidence). NEUROLOGY 2002;58:11–17 Mission statement. The Quality Standards Subcommittee of the American Academy of Neurology is charged with developing practice parameters for neurologists for diagnostic procedures, treatment modalities, and clinical disorders. The selection of topics for which practice parameters are used is based on prevalence, frequency of use, economic impact, membership involvement, controversy, urgency, external constraints, and resources required. Parkinson’s disease (PD) is a common neurodegenerative disorder with an estimated prevalence of 100 to 200/100,000 population. As it is a progressive disorder that results in significant disability 10 to 15 years after onset, the financial and social burden of this disease is considerable,1 particularly with our aging population. The worldwide cost of medications alone is estimated to be US $11 billion per year, with costs increasing threeto fivefold for patients with advanced disease.2,3 Ideally, if a drug were available, initial treatment of PD should slow disease progression. Once symptomatic benefit is required, treatment should reduce disability without inducing complications over the long term. Based on these goals, there are several controversial questions regarding initial PD treatment. These include: Does selegiline have neuroprotective benefit in the treatment of early PD? What is the best agent to initiate specific dopaminergic therapy in early PD? Finally, is there a benefit of sustained-release levodopa over immediate-release levodopa in the treatment of early PD? The 1993 AAN Practice Parameter examined anticholinergics, amantadine, selegiline, dopamine agonists, and levodopa in the treatment of PD.4 The conclusions were that: 1. Levodopa is usually the most effective on average of all the drugs for symptoms of PD, especially for bradykinesia or rigidity (class I, II, III) (table 1). 2. Anticholinergic agents are commonly used as iniApproved by the Quality Standards Subcommittee on August 11, 2001. Approved by the Practice Committee on October 17, 2001. Approved by the AAN Board of Directors on October 20, 2001. Address correspondence and reprint requests to the American Academy of Neurology, 1080 Montreal Avenue, St. Paul, MN 55116. Copyright © 2002 by AAN Enterprises, Inc. 11 tial therapy, especially in cases where tremor is predominant, but there is evidence that anticholinergic agents are better than levodopa for tremor (class II). 3. Amantadine has a modest effect on all features of the disease and has a low adverse effect profile (class II). 4. Dopamine agonists are effective for all features of the disease, but are not generally as effective as levodopa and are more expensive than levodopa (class I, II). 5. Selegiline. Class I evidence suggests a mild therapeutic and partial protective effect from selegiline, but confirmation of the neuroprotective effect is needed. Selegiline also has antidepressant activity that offers modest direct symptomatic benefit for PD (Evidence not classified in statement). Recent publications have compared levodopa directly to dopamine agonists (pramipexole, ropinirole and cabergoline)5-7 in treatment of de novo (previously untreated) patients with PD. These studies were a result of concern that early use of levodopa might predispose patients to develop long-term motor complications8 such as wearing off, dyskinesia, dystonia, and on-off phenomenon. Some studies have reported incidence of these complications as high as 80% in young patients and 44% in older patients after 5 years of levodopa treatment.9 The frequency of dyskinesias alone is reported to range between 30 and 80% after 5 to 7 years of levodopa use. Dyskinesias may become severe with pronounced interference in the performance of activities of daily living. Hence, quality of life can be negatively and significantly affected by dyskinesias. Increasing problems with motor fluctuations also leads to use of several different medications in combination, typically at higher doses.3,10,11 Ideally, patients should not have to choose between accepting the inevitability of dyskinesias or unacceptable levels of disability. The goal of treatment should be to obtain an optimal reduction of parkinsonism with a minimal risk of long-term side effects. In an effort to decrease the risk of motor complications, attention has turned to initial use of dopamine agonists as monotherapy. Historically, dopamine agonist monotherapy has been thought to be poorly tolerated with decreased efficacy and a delay in onset of symptomatic benefit in comparison with levodopa.12-15 This may not be the case with newer agonists. In addition, one of the theoretical benefits of dopamine agonists over levodopa is a longer halflife resulting in less pulsatile stimulation of dopamine receptors. This may reduce the risk of the development of dyskinesias and motor fluctuations.16,17 The common occurrence of the wearing-off phenomenon (end of dose bradykinesia) with immediate-release levodopa led to the development of sustained-release levodopa.16,17 Whether motor complications are influenced by initial symptomatic treatment of PD with sustained-release levodopa versus immediate-release levodopa was investigated. Evidence comparing these two levodopa preparations is evaluated. Literature review. To prepare this report, experienced neurologists with special expertise in PD were appointed by the Quality Standards Subcommittee (QSS). The English literature between 1966 and 2000 was searched using MEDLINE, EMBASE, and the Cochrane Library. The key words used were: early or de novo Parkinson’s disease, human trials, double-blind method. Since the effectiveness of levodopa and dopamine agonists compared with placebo in the treatment of early PD is established, we focused on studies comparing dopamine agonists with levodopa. Articles were identified using the generic term dopamine agonist or specific drug names (bromocriptine, cabergoline, pergolide, lisuride, pramipexole, ropinirole). Similarly, for controlled-release versus regular or immediate-release levodopa, comparator only studies were used. In examining the neuroprotective effects of selegiline, only studies in de novo patients were evaluated. Given the controversy generated by the report of Lees et al.18 that mortality was increased in patients with PD taking selegiline, studies utilizing selegiline in patients already receiving symptomatic therapy were included to address the safety of selegiline in this patient population. The results of the literature search were as follows: 38 articles for selegiline were identified, two of which addressed the issue of neuroprotection. Articles were rejected for the following reasons: 13 utilized selegiline as adjunctive treatment, 5 examined symptomatic benefit only, 5 examined nonmotoric effects of selegiline, 3 were repeat publications, 3 were interim reports, 3 were commentaries on ongoing research, and 1 was a review, not a meta-analysis. Three articles addressing safety of selegiline in PD were reviewed. Seventy-eight articles for dopamine agonists used as monotherapy in de novo patients were identified; only three were long-term studies (2 years or longer) fulfilling AAN criteria for level I or II evidence (criteria defined in table 2). Articles were rejected for the following reasons: 36 utilized the dopamine agonist as adjunctive treatment, 19 did not use a levodopa (active) control, 5 utilized nonmotor endpoints, 5 provided level IV evidence, 4 were open-label studies, 3 were interim reports with subsequent publication of the complete study, 2 were repeat publications, 1 was a review article, not a meta-analysis, and 1 was a report of human toxicity. Only one article was found that examined immediateTable 1 Levels of evidence employed in 1993 Class I Evidence provided by one or more well-designed, randomized, controlled clinical trials. Class II Evidence provided by one or more well-designed clinical studies such as case control, cohort studies,