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Levodopa-induced dyskinesia in Parkinson’s disease: Still no proof? A meta-analysis.

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Journal Journal of neural transmission (Vienna, Austria : 1996)
Year 2018
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This article includes 14 Primary studies 13 Primary studies (14 references)

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We investigated whether there is a linear relationship between levodopa (LD) dose and treatment duration, and the development of levodopa-induced dyskinesia (LID) among patients with early untreated Parkinson’s disease (PD). We performed a meta-analysis of randomized-controlled trials (RCTs) comparing LD monotherapy to any other antiparkinsonian treatment in early PD patients. Meta-regressions were conducted including as covariates the effects of LD dose, treatment duration, and age. We further proceeded in subgroup analyses based on the type of medications in the non-LD monotherapy (control) group and on whether patients in the control group received additional levodopa or not. Thirteen eligible RCTs were included, which revealed a significantly higher risk for dyskinesia in patients initially treated with LD monotherapy compared to any other treatment (OR = 2.82). None of the subsequent meta-regressions revealed any significant relationship with dose, treatment duration or age. Patients treated on LD monotherapy or MAOΙ plus LD were at a greater risk to develop LID than patients who received DA only or DA plus supplemental LD. The increased heterogeneity compromised the robustness of the results. The alleged correlation between LID and LD dose and treatment duration cannot be verified based on the data available so far. Well-designed, large-scale, long-term, RCTs on drug-naïve PD patients could allow the better comprehension of the pattern of the association between LID and LD treatment parameters. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Systematic review

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Comparison of the Efficacy of Different Drugs on Non-Motor Symptoms of Parkinson's Disease: a Network Meta-Analysis.

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Authors Li BD , Cui JJ , Song J , Qi C , Ma PF , Wang YR , Bai J
Journal Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
Year 2018
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This article includes 21 Primary studies 21 Primary studies (21 references)

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BACKGROUND/AIMS: A network meta-analysis is used to compare the efficacy of ropinirole, rasagiline, rotigotine, entacapone, apomorphine, pramipexole, sumanirole, bromocriptine, piribedil and levodopa, with placebo as a control, for non-motor symptoms in Parkinson's disease (PD). METHODS: PubMed, Embase and the Cochrane Library were searched from their establishment dates up to January 2017 for randomized controlled trials (RCTs) investigating the efficacy of the above ten drugs on the non-motor symptoms of PD. A network meta-analysis combined the evidence from direct comparisons and indirect comparisons and evaluated the pooled weighted mean difference (WMD) values and surfaces under the cumulative ranking curves (SUCRA). The network meta-analysis included 21 RCTs. RESULTS: The analysis results indicated that, using the United Parkinson's Disease Rating Scale (UPDRS) III, the efficacies of placebo, ropinirole, rasagiline, rotigotine, entacapone, pramipexole, sumanirole and levodopa in treating PD were lower than that of apomorphine (WMD = -10.90, 95% CI = -16.12∼-5.48; WMD = -11.85, 95% CI = -17.31∼-6.16; WMD = -11.15, 95% CI = -16.64∼-5.04; WMD = -11.70, 95% CI = -16.98∼-5.60; WMD = -11.04, 95% CI = -16.97∼-5.34; WMD = -13.27, 95% CI = -19.22∼-7.40; WMD = -10.25, 95% CI = -15.66∼-4.32; and WMD = -11.60, 95% CI = -17.89∼-5.57, respectively). Treatment with ropinirole, rasagiline, rotigotine, entacapone, pramipexole, sumanirole, bromocriptine, piribedil or levodopa, with placebo as a control, on PD exhibited no significant differences on PD symptoms when the UPDRS II was used for evaluation. Moreover, using the UPDRS III, the SUCRA values indicated that a pomorphine had the best efficacy on the non-motor symptoms of PD (99.0%). Using the UPDRS II, the SUCRA values for ropinirole, rasagiline, rotigotine, entacapone, pramipexole, sumanirole, bromocriptine, piribedil and levodopa treatments, with placebo as a control, indicated that bromocriptine showed the best efficacy on the non-motor symptoms of PD (75.6%). CONCLUSION: Among ropinirole, rasagiline, rotigotine, entacapone, apomorphine, pramipexole, sumanirole, bromocriptine, piribedil and levodopa, with placebo as a control, apomorphine may be the most efficacious drug for therapy in treating the non-motor symptoms of PD.

Systematic review

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Comparison for Efficacy and Tolerability among Ten Drugs for Treatment of Parkinson's Disease: A Network Meta-Analysis.

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Authors Zhuo C , Zhu X , Jiang R , Ji F , Su Z , Xue R , Zhou Y
Journal Scientific reports
Year 2017
Links Pubmed DOI PubMed Central

This article includes 109 Primary studies 100 Primary studies (109 references)

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Parkinson's disease (PD) is a long term disorder affects the central nervous system and we aim to determine the relative efficacy of the current available drugs used in PD. Firstly, we performed a systematic review in current literature and eligible studies were retrieved from online databases, relevant data were extracted. Efficacy of these medications was assessed by different Unified Parkinson's Disease Rating Scales (UPDRS). Mean difference (MD) and odds ratio (OR) were produced by pairwise or network meta-analysis (NMA). Finally, we performed a cluster analysis for the included medications with respect to their surface under the cumulative ranking curve (SUCRA). Pairwise meta-analysis suggests that selegiline had a higher ranking in UPDRS II, UPDRS III and UPDRS total than bromocriptine and levodopa. Selegiline was more tolerable than bromocriptine (OR = 0.62, CI: 0.39 to 0.98) and pramipexole was less tolerable than levodopa (OR = 1.43, CI = 1.00 to 2.04). Results of NMA indicate that patients with levodopa, pramipexole, ropinirole and selegiline exhibited a significantly improved UPDRS III than those with lazabemide. To sum up, levodopa, selegiline, ropinirole and rotigotine were recommended for PD patients as they appeared relatively high efficacy and tolerability.

Systematic review

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Levodopa alone compared with levodopa-sparing therapy as initial treatment for Parkinson's disease: a meta-analysis.

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Journal Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
Year 2015
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This article includes 11 Primary studies 7 Primary studies (11 references)

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To assess the long-term use of L-dopa alone vs L-dopa-sparing therapy, as initial treatment, provides the most efficient long-term control of symptoms and best quality of life for people with early Parkinson's disease (PD). PubMed; Google scholar; Cochrane Central Register of Controlled Trials and the Web of Science were searched for randomised, placebo-controlled trials (RCTs) on L-dopa alone and L-dopa sparing as initial treatment in early PD patients. We used a random effects model rather than a fixed effects model because of this takes into account heterogeneity between multi-studies. Eleven RCTs were included. The results showed that L-dopa alone could evidently improve the UPDRS part I (p = 0.005), part II (p < 0.0001), part III (p < 0.0001) and UPDRS total score (p = 0.004) compared with L-dopa-sparing therapy in PD patients. Meanwhile, a reduced risk of dyskinesia (p < 0.0001, RR = 1.88, 95 % CI 1. 37-2.59) and wearing-off phenomenon (p < 0.00001, RR = 1.36, 95 % CI 1. 20-1.55) in patients treated initially with L-dopa-sparing therapy compared to L-dopa has been consistently reported. What is more, we found more patients on aL-dopa-sparing therapy were more than triple as likely to discontinue treatment prematurely due to adverse events than L-dopa treatment patients (43.7 vs 15.8 %). L-Dopa alone is the most effective medication available for treating the motor symptoms of PD patients, despite the greater incidence of involuntary movements. Meanwhile, more patients on dopamine agonists or MAOBI were more likely to discontinue treatment prematurely than L-dopa alone treatment patients within the long follow-up period.

Systematic review

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Nonergot dopamine-receptor agonists for treating Parkinson's disease - A network meta-analysis

Authors Thorlund K , Wu P , Druyts E , Eapen S , Mills EJ
Journal Neuropsychiatric disease and treatment
Year 2014
Links Pubmed DOI PubMed Central

This article includes 45 Primary studies 45 Primary studies (45 references)

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Objective: To compare the efficacy of the three nonergot dopamine-receptor agonists (DAs) pramipexole, ropinirole, and rotigotine for the treatment of early and advanced Parkinson's disease (PD). Materials and methods: Bayesian network meta-analyses were performed separately for early and advanced PD, and at time points 11-16 and 24-28 weeks. Outcomes for early PD included improvement on the Unified Parkinson's Disease Rating Scale (UPDRS) activities in daily life (UPDRS-II), motor function (UPDRS-III), and their subtotal (UPDRS-II + III). Outcomes for advanced PD also included daily "off time" (hours), but not UPDRS-II + III. Results: Totals of 23 and 24 trials informed early and advanced PD analyses. For early PD UPDRS-II at 11-16 weeks, pramipexole and rotigotine were statistically significantly superior to placebo, but ropinirole was not. For UPDRS-III and UPDRS-II + III, all DAs were statistically significantly better than placebo and exhibited similar improvements. At 24-28 weeks, results were also statistically significant for all DAs versus placebo, and the magnitudes of improvements were similar for pramipexole, ropinirole and rotigotine. Advanced PD improvements on UPDRS-II, UPRDS-III, and off time were statistically significant for pramipexole, ropinirole, and rotigotine versus placebo. At 11-16 weeks, rotigotine yielded slightly smaller effects than ropinirole and pramipexole, but credible intervals on differences were wide. For off time, results were near identical. At 24-28 weeks, results were similar for all three outcomes. Ropinirole yielded a slightly higher improvement on UPDRS-III, but a slightly smaller improvement in off time. Conclusion: Our analyses suggest that pramipexole, ropinirole, and rotigotine exhibit similar efficacy in the treatment of early and advanced PD. © 2014 Thorlund et al.

Systematic review

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Mortality in Parkinson's disease: a systematic review and meta-analysis.

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Journal Movement disorders : official journal of the Movement Disorder Society
Year 2014
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This article includes 140 Primary studies 136 Primary studies (140 references)

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This study was undertaken to perform a systematic review and meta-analysis of studies of mortality in Parkinson's disease (PD) and to investigate which factors were associated with mortality. We conducted comprehensive searches of studies reporting a ratio of mortality in PD versus controls, descriptive survival measures, or factors predicting survival; assessed study quality; and extracted relevant data. Descriptive analysis, meta-analysis, and meta-regression were performed as appropriate. Eighty-eight studies were included in the review with variable study methods and quality. Almost all studies reported increased mortality in PD (vs. controls), with mortality ratios ranging from 0.9 to 3.8, with major between-study heterogeneity. Inception cohorts were more consistent with a pooled mortality ratio of approximately 1.5. Inception cohorts, measurements at longer follow-up duration, and older study recruitment year were associated with lower mortality ratios, but these findings were not robust in sensitivity analyses. Within studies, mortality ratios increased over time. No robust evidence was found that mortality has decreased after the introduction of levodopa (L-dopa). On average, PD survival reduced by approximately 5% every year of follow-up, although there was significant heterogeneity. In post-mortem studies, mean duration until death ranged from 6.9 to 14.3 years. Increasing age and presence of dementia were most commonly associated with increased mortality. Parkinson's disease is associated with increased mortality, but major heterogeneity is seen in estimates of mortality, which is probably explained by variable methodology and patient selection. Individual-patient-data meta-analysis of high-quality inception studies with long-term follow-up would be the optimal way to investigate the factors influencing mortality.

Systematic review

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The role of dopamine replacement on the behavioural phenotype of Parkinson’s disease.

Authors Alobaidi H , Pall H
Journal Behavioural neurology
Year 2013
Links Pubmed DOI PubMed Central

This article includes 16 Primary studies 16 Primary studies (16 references)

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OBJECTIVES: The pharmacotherapy of Parkinson’s disease (PD) is often challenging as clinicians have to find a favourable balance between the efficacy on motor symptoms and side effect profiles of different dopaminergic medications. We aimed to assess the available evidence on the role of dopamine agonist monotherapy as an alternative to Levodopa in the treatment of motor symptoms of PD, along with the role of dopamine antagonists in the treatment of PD-related psychosis. METHODS: We performed a systematic literature review using the databases MEDLINE, EMBASE, PsycINFO and the Cochrane Library Central register of controlled trials. Two searches were performed, ‘Search 1’ extracting trials on dopamine agonists, and ‘Search 2’ on atypical antipsychotics. Eligible studies were Double-blind Randomised Controlled Trials (RCTs) using the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Brief Psychiatric Rating Scale (BPRS) as outcome measures for Search 1 and 2, respectively. RESULTS: 16 relevant RCTs were extracted from the search results. Overall, dopamine agonists were shown to significantly improve UPDRS scores, with a mean percentage improvement of 14.4% compared to −1.9% in the control arm (P value &lt; 0.05). However, their side effect profile illustrated they were associated with twice the incidence of psychotic symptoms in comparison to the controls. The results on the efficacy of atypical antipsychotics for the treatment of PD-related psychosis were not significant. CONCLUSIONS: This evidence-based review confirmed that dopamine agonists can be an effective and safe treatment as monotherapy in PD, however psychotic symptoms remain a significant side effect. Atypical antipsychotics may not be relied upon for the correction of these symptoms due to inconsistent results about their efficacy. (PsycInfo Database Record (c) 2025 APA, all rights reserved)

Systematic review

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Tolerability and Safety of Ropinirole versus Other Dopamine Agonists and Levodopa in the Treatment of Parkinsons Disease: Meta-Analysis of Randomized Controlled Trials

Journal Drug safety : an international journal of medical toxicology and drug experience
Year 2010
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This article is included in 1 Structured summary of systematic reviews 40 Structured summaries of systematic reviews (1 reference)

This article includes 40 Primary studies 40 Primary studies (40 references)

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Background: Dopamine agonists have a well established role in the treatment of Parkinson's disease. The choice of a particular dopamine agonist requires assessing the benefit-risk balance of each available medication. Objective: The present study evaluated the tolerability and safety of ropinirole against those of other dopamine agonists (bromocriptine, cabergoline, pramipexole, rotigotine, pergolide) and placebo in monotherapy and adjuvant therapy with levodopa in the treatment of Parkinson's disease, as reported in the peer reviewed medical literature. Methods: A systematic review of the medical literature was carried out for relevant English language articles in the MEDLINE database and Cochrane Library from January 1975 to November 2008. The searches were limited to either double-blind clinical trials or randomized clinical trials that included both patients with early Parkinson's disease receiving dopamine agonist monotherapy, and patients at a later stage on combined treatment with levodopa. The Cochrane Collaboration guidelines were followed and the following data were extracted from each study: identifier (title and bibliographical reference), classification of the quality of the evidence (Jadad criteria), type and design of the study, number of patients, patient demographics (average age, sex), Parkinson's disease stage (Hoehn and Yahr Scale), treatment (monotherapy or adjuvant to levodopa), drugs used (including dosage and duration), study objective (safety or tolerability), method of evaluation of results, randomization and blinding, and description of all the adverse events in all treatment groups. A meta-analysis was performed, calculating relative risks (RRs) and confidence intervals for the 12 most relevant adverse events. On the basis of incidence and clinical importance criteria, the final selection of 12 adverse events was made by consensus between the investigators. Results: Forty randomized clinical trials were included. Direct comparison of ropinirole with bromocriptine showed a lower RR of constipation for ropinirole (0.55 [95% CI 0.35, 0.89]), while the direct comparison with levodopa showed a lower RR of dyskinesia for ropinirole (0.25 [95% CI 0.09, 0.71]); no significant differences for either dyskinesia or constipation were found when a direct comparison of ropinirole and rotigotine was made. For nausea, ropinirole, pergolide and rotigotine versus placebo all demonstrated similar RRs (2.25 [95%CI 1.85, 2.74]; 2.28 [95%CI 1.54, 3.37]; and 2.08 [95%CI 1.30, 3.34], respectively). On indirect comparison of ropinirole with pramipexole, ropinirole showed a higher RR for nausea (2.25 [95% CI 1.85, 2.74] vs 1.48 [95% CI 1.24, 1.76]), dizziness (1.87 [95% CI 1.48, 2.37] vs 1.20 [95% CI 1.01, 1.43]), somnolence (2.45 [95% CI 1.30, 4.61] vs 1.68 [95% CI 1.25, 2.25]), and dyskinesia (2.71 [95% CI 1.74, 4.21] vs 2.27 [95% CI 1.58, 3.27]). Pramipexole (3.36 [95% CI 2.41, 4.68], pergolide (4.80 [95% CI 2.24, 10.29]), ropinirole (2.84 [95% CI 1.34, 5.99]), and rotigotine (4.02 [95% CI 1.23, 13.11]) all had a higher RR of hallucinations compared with placebo. Pramipexole also showed a higher RR of confusion (2.64 [95% CI 1.18, 5.91]) and constipation (2.23 [95% CI 1.53, 3.25]) compared with placebo. Conclusions: In all the included studies, dopamine agonists, including ropinirole, exhibited a higher incidence of adverse events than placebo. Ropinirole showed an adverse event profile similar to other dopamine agonists. Consideration of the clinical characteristics of each patient and the differences in the incidence of adverse events related to each dopamine agonist, may help to optimize the dopamine agonist therapy. © 2010 Adis Data Information BV. All rights reserved.

Systematic review

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Dopamine agonists in the treatment of early Parkinson's disease: A meta-analysis

Journal Parkinsonism & related disorders
Year 2009
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This article is included in 1 Structured summary of systematic reviews 24 Structured summaries of systematic reviews (1 reference)

This article includes 25 Primary studies 24 Primary studies (25 references)

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Our objective was to perform a meta-analysis of randomized controlled trials of dopamine agonists (DA) as monotherapy as well as adjunctive therapy for the early treatment of Parkinson's disease (PD). A systematic literature search was conducted through April 2007. Both efficacy and safety endpoints were evaluated. DA monotherapy showed superior efficacy but more frequent adverse events compared to placebo. In addition, DA demonstrated inferior efficacy to levodopa, but was associated with fewer motor complications. However, DAs were associated with a greater incidence of nuisance side effects, such as hallucinations, somnolence and dizziness. The use of DA is an effective treatment option for the treatment of early PD and appears especially useful among PD patients with wearing-off phenomenon or dyskinesias on levodopa; however it may result in more adverse events and higher withdrawal rates. © 2008 Elsevier Ltd. All rights reserved.

Systematic review

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Dopamine agonist therapy in early Parkinson's disease

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Journal Cochrane database of systematic reviews (Online)
Year 2008
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This article includes 35 Primary studies 29 Primary studies (35 references)

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BACKGROUND: Dopamine agonists are being used increasingly as first line treatment for Parkinson's disease, but there remains uncertainty 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 to placebo or levodopa in early Parkinson's disease. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library), MEDLINE, EMBASE, PubMed, LILACS and Web of Science, plus major journals in the field, abstract books, conference proceedings and reference lists of retrieved publications. SELECTION CRITERIA: Randomised 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's disease. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data on clinician-rated disability, motor complications, other side-effects, treatment concordance, levodopa dose and mortality. MAIN RESULTS: Twenty-nine eligible trials, involving 5247 participants, were identified. Participants randomised 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 &lt; 0.00001), dystonia (OR 0.64, 95% CI 0.51 to 0.81; P = 0.0002) and motor fluctuations (OR 0.75, 95% CI 0.63 to 0.90; P = 0.002) than levodopa-treated participants. However, various 'non-motor' side-effects, including oedema (OR 3.68, 95% CI 2.62 to 5.18; P &lt; 0.00001), somnolence (OR 1.49, 95% CI 1.12 to 2.00; P = 0.007), constipation (OR 1.59, 95% CI 1.11 to 2.28; P = 0.01), dizziness (OR 1.45, 95% CI 1.09 to 1.92; P = 0.01), hallucinations (OR 1.69, 95% CI 1.13 to 2.52; P = 0.01) and nausea (OR 1.32, 95% CI 1.05 to 1.66; P = 0.02) were all increased in agonist-treated participants (compared with levodopa-treated participants). Agonist-treated participants were also significantly more likely to discontinue treatment due to adverse events (OR 2.49, 95% CI 2.08 to 2.98; P &lt; 0.00001). Finally symptomatic control of Parkinson's disease was better with levodopa than with agonists, but data were reported too inconsistently and incompletely to meta-analyse. AUTHORS' CONCLUSIONS: This meta-analysis confirms that motor complications are reduced with dopamine agonists compared to levodopa, but also establishes that other important side-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 to levodopa.