Long-acting Non-ergot Dopamineagonists In Parkinson’s Disease: A Systematic Reviewand Meta-analysis Of Randomized Controlled Trials

Parkinson’s disease (PD) is a chronic neurodegenerative disordercharacterized by symptoms of resting tremor, rigidity, bradykinesia, andpostural instability. The incidence of PD was approximately2.0%inChinese individuals. The etiology and pathogenesis of PD are complex andhave not been fully elucidated. However, the treatment at present is onlysymptomatic treatment and can not cure PD or delay the progression of PD.Levodopa has been considered as the most effective drug for PD, butthe initial therapeutic efficacy is often impacted within a few years by thedevelopment of motor complications (fluctuations, dyskinesias) that areintractable to treatment. It is now thought that pulsatile stimulation ofstriatal dopamine receptors, caused by intermittent administration oflevodopa and erratic gastrointestinal absorption, plays a key role in thedevelopment of these motor complications. Continuous dopaminergicstimulation and non-oral route of administration have been one of the mainissue of PD study. Dopamine agonists (DA) have been extensively used as monotherapyin early PD or as an adjunctive therapy to levodopa in advanced PD withmotor complications for many years. There is no strong evidence that agiven active agonist is more potent than another one, but ergot DA are nolonger used as first-line treatments of PD because of the risk of fibroticadverse reactions. However, non-ergot dopamine agonists (NEDA)continue to be used as first-line agents and new long-acting formulations ofNEDA, including the rotigotine transdermal patch, extended-releasepramipexole, and ropinirole prolonged-release, are now available.Compared with the three times daily administration of standard NEDA,once-daily administration of long-acting NEDA provide a more stableplasma concentration over24hours and more continuous dopaminergicstimulation. Furthermore, recent studies have demonstrated that once-dailyadministration of long-acting NEDA can improve patient comfort andadherence to treatment. Non-oral routes of rotigotine delivery areparticularly useful in patients scheduled for surgery or in those withdysphagia.Over the last decade, numerous randomized controlled trials (RCT)have been performed to evaluate the efficacy and safety of long-actingNEDA, but there are some questions:(1) One trial obtained concluded thatrotigotine transdermal patch was not superior to placebo. Moreover, crystalformation was noted in some rotigotine patches and these crystal-related changes may reduce its bioavailability and clinical efficacy.(2) The resultsof trials were not consistent: one trial concluded that long-acting NEDAwas superior to standard NEDA, some trials concluded that long-actingNEDA was noninferior to standard NEDA, and some trials did not showthe noninferiority.(3) Long-term (>2years) trials have not been conducted.(4) No meta-analysis of long-acting NEDA has been performed to providedata of evidence-based medicine to our knowledge. Therefore, in thepresent study, we pooled all of the available RCT results and performed acomprehensive meta-analysis to assess the efficacy, tolerability, and safetyof long-acting NEDA in PD.PART IROTIGOTINE TRANSDERMAL PATCH IN PARKINSON’SDISEASE:ASYSTEMATIC REVIEWAND META-ANALYSISOF RANDOMIZED CONTROLLED TRIALSObjective: To evaluate the efficacy, tolerability, and safety ofrotigotine transdermal patch versus placebo in Parkinson’s disease, weperformed a meta-analysis of randomized controlled trials (RCT).Methods: The PubMed, EMBASE, Cochrane Library databases, andWeb of Knowledge were searched up to July10th2012. The pooledweighted mean differences (WMD) and relative risks (RR) with95%confidence intervals (CI) were calculated. Review Manager software version5.1was used to analyze the data.Results:(1) Six large-scale RCT, involving1789patients, wereincluded in this meta-analysis.(2) The results of meta-analysis showed:①Efficacy: As compared with placebo, the use of rotigotine resulted ingreater improvements in UPDRS II score (WMD–1.69,95%CI–2.18to–1.19), III score (WMD–3.86,95%CI–4.86to–2.86), and the II and IIIsubtotal score (WMD–4.52,95%CI–5.86to–3.17).②Tolerability: Nodifferences were found in overall withdrawals (RR0.88,95%CI0.64to1.21), but rotigotine was associated with a significantly higher rate ofwithdrawals due to adverse events (RR1.82,95%CI1.29to2.59).③Safety: Rotigotine was associated with a significantly higher rate ofapplication site reactions (RR2.92,95%CI2.29to3.72), vomiting (RR5.18,95%CI2.25to11.93), and dyskinesia (RR2.52,95%CI1.47to4.32)compared with placebo. No differences were found in the relative risks ofheadache, constipation, back pain, diarrhea, or serious adverse events.Conclusions: Our meta-analysis showed that the use of rotigotine canreduce the symptoms of PD. However, rotigotine was also associated with ahigher incidence of adverse events, especially application site reactions,compared with placebo. PART IILONG-ACTING NON-ERGOT DOPAMINEAGONISTSVERSUS PLACEBO IN PARKINSON’S DISEASE:ASYSTEMATIC REVIEWAND META-ANALYSIS OFRANDOMIZED CONTROLLED TRIALSObjective: To evaluate the efficacy, tolerability, and safety ofnon-ergot dopamine agonists (NEDA) versus placebo in Parkinson’sdisease, we performed a meta-analysis of randomized controlled trials(RCT).Methods: The PubMed, EMBASE, Cochrane Library databases, andWeb of Knowledge were searched up to February10th2013. The pooledweighted mean differences (WMD) and relative risks (RR) with95%confidence intervals (CI) were calculated. Review Manager softwareversion5.1was used to analyze the data.Results:(1) Nine RCT (n=2857) which assessed the rotigotinetransdermal patch, extended-release pramipexole, and ropiniroleprolonged-release, were included in this meta-analysis.(2) The results ofmeta-analysis showed:①Efficacy: Compared with placebo, long-actingNEDA achieved greater improvements in UPDRS II score (WMD–1.77,95%CI–2.13to–1.41), III score (WMD–4.18,95%CI–4.94to–3.43)and the II and III subtotal score (WMD–5.12,95%CI–6.16to–4.07), aswell as a reduction in “off” time (WMD–1.29,95%CI–1.64to–0.93) and an increase in “on” time without troublesome dyskinesia (WMD1.55,95%CI1.06to2.04).②Tolerability: No differences were found in overallwithdrawals (RR0.91,95%CI0.69to1.20), but long-acting NEDA wasassociated with a significantly higher rate of withdrawals due to adverseevents (RR1.76,95%CI1.31to2.35).③Safety: Compared with placebo,long-acting NEDA were associated with a higher risk of nausea (RR2.11,95%CI1.71to2.61), but no difference was found in headache (RR1.35,95%CI0.99to1.84). Higher risks of dizziness, somnolence, constipation,vomiting, and insomnia were only found in early PD while higher risks ofdyskinesia and hallucination were only found in advanced PD.Conclusions: Our meta-analysis showed that the use of long-actingNEDA can reduce the symptoms of PD patients. However, long-actingNEDA were also associated with a higher incidence of adverse events,especially in early PD patients, compared with placebo. PART IIILONG-ACTING VERSUS STANDARD NON-ERGOTDOPAMINEAGONISTS IN PARKINSON’S DISEASE:ASYSTEMATIC REVIEWAND META-ANALYSIS OFRANDOMIZED CONTROLLED TRIALSObjective: To evaluate the efficacy, tolerability, and safety oflong-acting versus standard non-ergot dopamine agonists (NEDA) inParkinson’s disease, we performed a meta-analysis of randomizedcontrolled trials (RCT).Methods: The PubMed, EMBASE, Cochrane Library databases, andWeb of Knowledge were searched up to November20th2013. The pooledweighted mean differences (WMD) and relative risks (RR) with95%confidence intervals (CI) were calculated. Review Manager softwareversion5.1was used to analyze the data.Results:(1) Eight large-scale RCT, involving2392patients, wereincluded in this meta-analysis.(2) The results of meta-analysis showed:①Efficacy: Compared with the standard NEDA, long-acting NEDAexhibited similar improvements in UPDRS II score (WMD0.09,95%CI–0.33to0.50), III score (WMD–0.35,95%CI–1.60to0.90), and “off”time (WMD0.18,95%CI–0.14to0.50).②Tolerability: No differenceswere found in overall withdrawals (RR1.11,95%CI0.94to1.32),withdrawals due to adverse events (RR1.19,95%CI0.91to1.56) betweenthe two formulations.③Safety: No differences were found in the tencommonly reported adverse events between the two formulations.Conclusions: Our meta-analysis showed long-acting NEDA were noninferior to standard NEDA in efficacy, tolerability, and safety in thetreatment of Parkinson’s disease.