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Source: Askthedoctor-mailinglist Date: 13 january 2002 Orig. source: Neurology 2002;58:11-17 Orig. date: 9 january 2002 The following article appeared in Neurology, the official journal of the American Academy of Neurology. The article was modified by Dr. Lieberman so as to make it more readable by lay people with PD. Initiation of treatment for Parkinson’s disease. Report of the Quality Standards Subcommittee of the American Academy of Neurology. J.M. Miyasaki, MD (lead author) Abstract 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 nova 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 3) is there a benefit of sustained release levodopa over immediate-release levodopa? Using evidence-based principles, a literature review was performed to identify all human trials in de novo PD between 1966 and 1999. Based on this review, the authors conclude: 1) Selegiline has very mild symptomatic benefit with no evidence for neuroprotective benefit. 2) For PD patients requiring initiation of symptomatic therapy, either levodopa or a DA can be used. 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. NEUROLOGY 2002;58:11-17 Recent publications have compared levodopa directly to dopamine agonists (pramipexole, ropinirole and cabergoline) 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 complications such as wearing off, dyskinesia, dystonia, and on-off phenomenon. Some studies have reported incidence of these complications as highs as 80% in young patients and 44% in older patients after 5 years of levodopa treatment. The frequency of dyskinesias alone is reported to range between 30-80% 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. 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 agonists monotherapy has been thought to be poorly tolerated with decreased efficacy and a delay in onset of symptomatic benefit in comparison with levodopa. This may not be the case with newer agonists. In addition, one of the theoretical benefits of dopamine agonists over levodopa is a longer half-life resulting in less pulsatile stimulation of dopamine receptors. This may reduce the risk of the development of dyskinesias and motor fluctuations. The common occurrence of the wearing-off phenomenon (end of dose bradykinesia) with immediate-release levodopa led to the development of sustained-release levodopa. 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. Selegiline. What is the role of selegiline in the treatment of early PD? A neuroprotective benefit of selegiline through decreased free radical production was proposed and resulted in the DATATOP clinical trial. An interim analysis of the DATATOP trial demonstrated that selegiline reduced the risk of developing disability requiring levodopa therapy by 50%. The authors concluded, initially, that this was possibly consistent with a neuroprotective effect. Further follow-up of the patients revealed a symptomatic benefit of selegiline with a 17.2% absolute reduction in the risk of requiring levodopa by selegiline compared with placebo (indicating that selegiline did not slow the progression of PD rather that it had a mild effect on masking the symptoms of PD). In a second study examining this issue, Palhagen and associates found a 4-month delay to requiring levodopa in those randomized to selegiline. The rate of decline of the motor scores was significantly slower at 6 months. Additionally, the rate of decline of motor scores from baseline to the end of the washout was significantly slower for the selegiline-treated patients. Since both groups found an initial decline in disability during the 2-month washout period, it must be concluded that symptomatic benefit at least partially explained the reduced risk of requiring levodopa. In addition, if selegiline had neuroprotective effects, those taking selegiline for a longer period of time would be expected to show less evidence of disease progression compared with those starting it later in the course of the disease. Once levodopa was initiated, motor complications would be expected to be less frequent in those who had received selegiline than in those who had not. Neither of these expectations was realized, further supporting the idea that the symptomatic effects of selegiline accounted for the delay in the need for levodopa therapy. One study raised the issue of the safety of selegiline. Lees and associates in the United Kingdom reported a significant excess mortality in patients receiving selegiline with levodopa alone (76 deaths from among 271 patients treated with selegiline for several years) compared with those receiving levodopa alone (44 deaths from among 249 treated with levodopa over a comparable number of years). Concerns about the conduct and the conclusions from this study were many. An analysis of subsequent prospective trials in the United Kingdom with long-term follow-up including patients with similar exposure to selegiline as in the Lees study was performed. There was no difference in mortality between selegiline and nonselegiline treatment groups (selegiline does not increase the risk of death in PD). The Parkinson Study Group (PSG) in the United States reported that there was no difference in mortality in the 800 original DATATOP subjects who had been assigned to selegiline after an average follow-up of 8.2 years. The mortality rate observed in these patients was very similar to that expected in the age- and sex-matched US population. Conclusions. Selegiline has mild symptomatic benefit. There is no convincing clinical evidence for neuroprotective benefit with selegiline. There is no convincing evidence for increased mortality with selegiline whether it is given in combination with levodopa or as monotherapy. Starting Treatment When symptomatic therapy is required does levodopa or dopamine agonist offer best control of motor symptoms? Once disability in PD requires treatment with a dopaminergic agent, the choice of levodopa versus a dopamine agonist has been arbitrary. Decades of debate concerning this issue did not clarify the choice because the trials conducted in those years were inadequate to answer the question. In this evidenced based-review, three studies compared the effect of a single agonist versus levodopa in the treatment of PD patients who were not receiving dopamine agonist or levodopa therapy. Each-study was designed to allow the addition of open-label levodopa to “rescue” patients who were not doing well motorically. The study of cabergoline (not available in the United States) versus levodopa found that the motor portion of the UPDRS decreased by 40-50% with both drugs during the first year of therapy. Overall, however, levodopa appeared to be better than cabergoline for improvement. After 4 years in the trial, levodopa subjects still showed an average of 30% improvement in motor disability while patients treated with cabergoline showed a 22 % improvement. The study of ropinirole (Requip) versus levodopa found that for patients who completed the study (5 years), levodopa treatment resulted in a greater increase in motor improvement than did ropinirole treatment. They also reported that, overall, there was no difference between the treatment groups at 5 years with regard to score on the activities of daily living portion of the UPDRS (this may be a better over-all measure of how people with PD are doing). The study of pramipexole (Mirapex) versus levodopa by the Parkinson Study Group was assessed as being the best of the three studies. This study found that after 23.5 months of treatment, levodopa resulted in a greater improvement that pramipexole in both the motor and activities of daily living portions of the UPDRS. Conclusions. Levodopa, cabergoline, ropinirole, and pramipexole are effective in reducing motor and ADL disability in patients with PD who require dopaminergic therapy. Levodopa is more effective than cabergoline, ropinirole, and pramipexole in treating the motor and activities of daily living features of PD. When symptomatic therapy is required, does levodopa or a dopamine agonist offer the most favorable long-term complication profile? All three studies demonstrated that levodopa, cabergoline, ropinirole, or pramipexole have efficacy in alleviating motor symptoms of PD. All three studies defined motor complications differently. The cabergoline study used a checklist of symptoms suggesting motor fluctuations to determine the endpoint. The motor fluctuation abnormalities had to be present on two subsequent study visit to be considered present. Motor fluctuations in this study included wearing off, dyskinesias, and random freezing (which were also evaluated in the ropinirole and pramipexole studies). The motor complications checklist in the cabergoline study also included nocturnal akinesia, early morning akinesia, “off” period freezing, early morning dystonia, dose-related “off” period dystonia, and dose-related “on” period dystonia. These latter items were not evaluated in the ropinirole or pramipexole studies. The cabergoline study found an absolute risk reduction of 12% for the development of “motor complications” during the study comparing this agonist (with or without levodopa rescue) to levodopa. The motor complication endpoint was reached in 22% of patients treated with cabergoline versus 34% treated with levodopa. The median duration of treatment was 3.7 years. At the time of reporting, 35% of patients could be satisfactorily managed on cabergoline alone. Patients included in this analysis were treated for at least 3 years and up to 5 years. Adverse events were higher in the cabergoline group (75%) versus levodopa (65%), with nausea being the most common in both. In the study of ropinirole versus levodopa, the primary endpoint was dyskinesias rather than other types of motor complications. The absolute risk reduction for dyskinesias after 5 years of treatment was 26% for the ropinirole group (monotherapy or with the later addition of levodopa adjunctive therapy). Adverse events were similar in the levodopa and ropinirole monotherapy groups, with the two most common reasons for dropping out of the study being nausea and hallucinations. The incidence of hallucinations was higher in the ropinirole group ( 17%) than in the levodopa group ( 6%), as was the incidence of edema of the legs (14%; versus levodopa 6%) and drowsiness (27%; versus levodopa 19%). However, dropout rates due to adverse events were no different in the two treatment groups. Retention of patients in the 5-year study was 47% for the ropinirole group and 50% for the levodopa group. Among patients who completed the study and were originally randomized to ropinirole monotherapy, 16% were maintained on ropinirole monotherapy for 5 years. A lower percentage of the levodopa group required the addition of more levodopa. The results demonstrate that initiation of treatment with ropinirole and the later addition of levodopa as necessary resulted in a significantly lower incidence of dyskinesia compared with levodopa alone. The Parkinson Study Group study of pramipexole (Mirapex) versus levodopa monotherapy in PD demonstrated similar findings. Motor complications, defined as dyskinesias, wearing off, and on-off motor fluctuations, were significantly less common in the pramipexole group (28%) versus levodopa-treated patients (51%) at the end of 23.5 months. Motor complications also occurred less frequently in the pramipexole-treatment group in each of the four 6-month study periods. 32% of the originally randomized group of pramipexole monotherapy patients were maintained on monotherapy until the end of the study. This study also examined the impact of treatment on the quality of life of patients using the PD Quality of Life Scale and the European quality of life. During the first 78 weeks of the trial, there was no difference in quality of life measures for either treatment group. At 102 weeks, a significant group difference in the PD Quality of Life in favor of the levodopa group was detected. More patients in the pramipexole group experienced drowsiness, hallucinations, and edema compared with those in the levodopa group. As noted in the 1993 practice parameter on this subject, treatment with dopamine agonists is more costly than the use of levodopa. This remains true. Conclusions. Cabergoline, ropinirole, pramipexole treatment of PD patients requiring dopaminergic therapy results in fewer motor complications wearing off, dyskinesias, on-off motor fluctuations) than levodopa treatment after 2.5 years of follow-up. Cabergoline, ropinirole, and pramipexole treatment of PD patients requiring dopaminergic therapy is associated with more frequent hallucinations, drowsiness, and edema than levodopa therapy. Recommendations. In patients with PD who require the initiation of dopaminergic treatment, either levodopa or a dopamine agonist may be used. The choice depends on the relative impact of improving motor disability (better with levodopa) compared with the lessening of motor complications (better with dopamine agonists) for each individual patient with PD. Sustained-release versus immediate release levodopa: When initiating levodopa therapy, which formulation should be used-immediate-release or sustained-release levodopa? Only one study compared sustained-release and immediate-release formulations of levodopa in a prospective, randomized, double-blind manner. The 5-year study (“CR First”) had an overall low rate of dyskinesias (20% immediate-release Sinemet versus 21% in the Sinemet CR group. The only difference detected between the treatment groups was a greater improvement in activities of daily living scores in the Sinemet CR group. The results of this study do not demonstrate sufficient differences to recommend controlled-release levodopa over immediate-release levodopa when initiating levodopa treatment. Conclusions. When initiating therapy with levodopa, there is no difference in the rate of motor complications between immediate-release levodopa and sustained- release levodopa. Recommendations. For patients with PD in whom levodopa treatment is being instituted, either an immediate-release or sustained-release preparations may be considered. ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn