In recent years, a few of randomized controlled trials (RCTs) about amantadine for treating dyskinesia in Parkinson's disease (PD) were completed. Here, we conducted a systematic literature review about the clinical research to provide the updated evidence for treating dyskinesia. Electronic search of Medline, PubMed, Cochrane Library, and other databases up to May 2016 for relevant studies was performed. We selected the Unified Parkinson's Disease Rating Scale IV (UPDRS IV) and Dyskinesia Rating Scales (DRS) as efficacy outcomes of amantadine on dyskinesia. Pooled data from included studies was then used to carry out meta-analysis. A total of eleven eligible RCTs that involved 356 PD patients with existing dyskinesia were included in the present study. The results of meta-analysis showed that amantadine significantly improved UPDRS IV (P < 0.0001) and DRS (P < 0.00001). Meanwhile, there was a mild reduction in Unified Parkinson's Disease Rating Scale III after amantadine treatment in advanced PD patients with dyskinesia (P = 0.01) compared with placebo. High dosage of amantadine obviously improved existing dyskinesia in PD, yet at the expense of the increased adverse events. It was necessary to detect the optimal therapeutic efficacy to balance the incidence of adverse events when we used amantadine to treat existing dyskinesia in PD patients.
BACKGROUND: Levodopa-induced dyskinesias (LID) are amongst the most disabling side-effects of levodopa therapy for Parkinson's disease (PD). It has been suggested that that N-Methyl-D-Aspartate (NMDA)-receptor antagonist may reduce peak-dose dyskinesia in PD patients and may lead to motor improvement. In this study, we compared the efficacy of NMDA receptor antagonists versus placebo in the treatment of LID in PD through a meta-analysis of controlled trials.
METHODS: Electronic search of Pubmed (1990 - 2010), Medline (1966-2010), EMBASE (1974-2010) and other databases for relevant studies were performed. Controlled clinical trials of the effects of NMDA antagonists on LID that fulfill the study protocol were selected. Pooled data from included studies was then used to perform random and fixed effect models meta-analysis.
RESULTS: The search resulted in 11 randomized, placebo controlled clinical trials that involved a total of 253 PD patients with peak-dose LID. The outcome measures were various dyskinesia rating scales and the Unified Parkinson Disease Rating Scale (UPDRS) subscales III and IV. The analysis showed significant reduction in Standard Mean Difference (SMD) for UPDRS IV (SMD -1.45; 95%CI -2.28 to -0.63) and UPDRS III (SMD -0.41; 95%CI -0.69 to -0.12) after treatment with amantadine. Other included drugs did not show significant change in the outcomes measured.
CONCLUSION: This meta-analysis provides an update on the clinical trials and confirms the short-term benefits of amantadine therapy in the treatment of dyskinesia. The effects of other NMDA receptor antagonists need to be evaluated further in clinical trials.
BACKGROUND: Abnormal involuntary movements known as dyskinesias are amongst the most disabling side-effects of levodopa therapy. It is thought that amantadine, an NMDA-receptor antagonist, may reduce dyskinesias in patients with Parkinson's disease without worsening Parkinsonian symptoms.
OBJECTIVES: To compare the efficacy and safety of adjuvant amantadine therapy versus placebo in treating dyskinesia in patients with Parkinson's disease, already established on levodopa, and suffering from motor complications.
SEARCH STRATEGY: Electronic searches of The Cochrane Controlled Trials Register (The Cochrane Library Issue 3, 2001), MEDLINE (1966-2001), EMBASE (1974-2001), SCISEARCH (1974-2001), BIOSIS (1993-2001), GEROLIT (1979-2001), OLDMEDLINE (1957-1965), LILACS (1982-2001), MedCarib (17th Century - 2001), PASCAL (1973-2001), JICST-EPLUS (1985-2001), RUSSMED (1973-2001), DISSERTATION ABSTRACTS (2000-2001), SIGLE (1980-2001), ISI-ISTP (1990-2001), Aslib Index to Theses (2001), Clinicaltrials.gov (2001), metaRegister of Controlled Trials (2001), NIDRR (2001) and NRR (2001) were conducted. Grey literature was hand searched and the reference lists of identified studies and reviews examined. The manufacturers of amantadine were contacted.
SELECTION CRITERIA: Randomised controlled trials comparing amantadine with placebo in the treatment of dyskinesia in patients with a clinical diagnosis of idiopathic Parkinson's disease.
DATA COLLECTION AND ANALYSIS: Data was abstracted independently by NC and KD onto standardised forms and disagreements were resolved by discussion.
MAIN RESULTS: Three randomised controlled trials were found comparing amantadine with placebo in the treatment of dyskinesia in patients with idiopathic Parkinson's disease. Three trials were excluded on the basis that they had no control group and a further three did not state whether they randomised the treatment that participants received. The included trials were double-blind cross-over studies involving a total of 53 patients. All three studies failed to present data from the first arm, instead presenting results as combined data from both treatment arms and both placebo arms. Two trials had no wash-out interval between the treatment periods. In view of the risk of a carry-over effect into the second arm, the results of these trials were not analysed. The final trial had a one week wash-out interval but only examined 11 participants. One study reported side-effects of amantadine in 8 of the 18 participants, including confusion and worsening of hallucinations. Another reported reversible edema of both feet in one of eleven participants.
AUTHORS' CONCLUSIONS: Due to lack of evidence it is impossible to determine whether amantadine is a safe and effective form of treatment for levodopa-induced dyskinesias in patients with Parkinson's disease.
BACKGROUND: Although levodopa is the most common drug prescribed to relieve the symptoms of Parkinson's disease it is associated with motor and psychiatric side-effects. Consequently, interest has turned to alternative drugs with improved side-effect profiles to replace or augment levodopa. Amantadine, originally used as an antiviral drug, has been shown to improve the symptoms of Parkinson's disease.
OBJECTIVES: To compare the efficacy and safety of amantadine therapy (monotherapy or adjuvant therapy) versus placebo in treating people with Parkinson's disease.
SEARCH STRATEGY: Electronic searches of The Cochrane Controlled Trials Register (The Cochrane Library Issue 3, 2001), MEDLINE (1966-2001), EMBASE (1974-2001), SCISEARCH (1974-2001), BIOSIS (1993-2001), GEROLIT (1979-2001), OLDMEDLINE (1957-1965), LILACS (1982-2001), MedCarib (17th Century - 2001), PASCAL (1973-2001), JICST-EPLUS (1985-2001), RUSSMED (1973-2001), DISSERTATION ABSTRACTS (2000-2001), SIGLE (1980-2001), ISI-ISTP (1990-2001), Aslib Index to Theses (2001), Clinicaltrials.gov (2001), metaRegister of Controlled Trials (2001), NIDRR (2001) and NRR (2001) were conducted. Grey literature was hand searched and the reference lists of identified studies and reviews examined. The manufacturers of amantadine were contacted.
SELECTION CRITERIA: Randomised controlled trials comparing amantadine with placebo in the treatment of patients with a clinical diagnosis of idiopathic Parkinson's disease.
DATA COLLECTION AND ANALYSIS: Data was abstracted independently by NC and KD onto standardised forms and disagreements were resolved by discussion.
MAIN RESULTS: Six randomised controlled trials were found comparing amantadine monotherapy or adjuvant therapy with placebo in the treatment of idiopathic Parkinson's disease. Five examined amantadine as adjuvant therapy with optimal levels of levodopa or anticholinergics and one examined amantadine as an adjuvant therapy with minimum tolerated levels of anticholinergics or as a monotherapy. Five were double-blind cross-over studies and one was a double-blind parallel group study. In total they examined 215 patients. The parallel group study allowed the randomisation codes to be broken and allowed patients in the placebo group to then receive amantadine. This could have led to bias. One study did not present the results of the placebo arm of the trial, hence we could not determine the difference between the two treatment groups. Two cross-over studies presented the results of the combined data from both treatment and placebo arms. The risk of carry-over effect into the second arm meant that these results could not be analysed. The final two studies presented at least some of their data from the end of the first arm of the trials. However only means were given, without standard deviations, so we could not determine the statistical significance of any difference between the amantadine and placebo groups. Although the authors did report on the side-effects from amantadine (such as livido recticularis, dry mouth and blurred vision), they state that none of them were severe.
AUTHORS' CONCLUSIONS: A considerable amount of evidence on the effectiveness of amantadine has accrued from non-controlled trials, often in patients with Parkinsonian conditions other than idiopathic Parkinson's disease. However, rigorous analysis of the six randomised controlled trials of amantadine reveals insufficient evidence of its efficacy and safety in the treatment of idiopathic Parkinson's disease.
In recent years, a few of randomized controlled trials (RCTs) about amantadine for treating dyskinesia in Parkinson's disease (PD) were completed. Here, we conducted a systematic literature review about the clinical research to provide the updated evidence for treating dyskinesia. Electronic search of Medline, PubMed, Cochrane Library, and other databases up to May 2016 for relevant studies was performed. We selected the Unified Parkinson's Disease Rating Scale IV (UPDRS IV) and Dyskinesia Rating Scales (DRS) as efficacy outcomes of amantadine on dyskinesia. Pooled data from included studies was then used to carry out meta-analysis. A total of eleven eligible RCTs that involved 356 PD patients with existing dyskinesia were included in the present study. The results of meta-analysis showed that amantadine significantly improved UPDRS IV (P < 0.0001) and DRS (P < 0.00001). Meanwhile, there was a mild reduction in Unified Parkinson's Disease Rating Scale III after amantadine treatment in advanced PD patients with dyskinesia (P = 0.01) compared with placebo. High dosage of amantadine obviously improved existing dyskinesia in PD, yet at the expense of the increased adverse events. It was necessary to detect the optimal therapeutic efficacy to balance the incidence of adverse events when we used amantadine to treat existing dyskinesia in PD patients.
