Adverse effects produced by different drugs used in the treatment of Parkinson s disease: A mixed treatment comparison

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1 Received: 10 May 2017 Revised: 7 August 2017 Accepted: 8 August 2017 DOI: /cns ORIGINAL ARTICLE Adverse effects produced by different drugs used in the treatment of Parkinson s disease: A mixed treatment comparison Bao-Dong Li 1 Zhen-Yun Bi 1 Jing-Feng Liu 1 Wei-Jun Si 1 Qian-Qian Shi 1 Li-Peng Xue 1 Jing Bai 2 1 Department of Neurology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China 2 Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China Correspondence Jing Bai, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China. drbaijing_bj@163.com Summary Objective: This mixed treatment comparison is used to compare the adverse effects of eleven different drugs used to treat Parkinson s disease (PD). The drugs that we compare include the following: ropinirole, rasagiline, rotigotine, entacapone, apomorphine, pramipexole, sumanirole, bromocriptine, piribedil, pergolide, and levodopa. Methods: PubMed, EMBASE, and Cochrane Library were searched from the inception to December Our analysis combines the evidences of direct comparison and indirect comparison between various literatures. We evaluated the merging odds ratios (OR) value and surface under the cumulative ranking curves (SUCRA) of each of the drugs and used this as a mode of comparison. Results: Twenty- four randomized controlled trials (RCTs) were included in this study. Our results demonstrated that the incidence of adverse reactions of ropinirole, rotigotine, entacapone, and sumanirole were obviously higher in terms of nausea compared to the placebo. Ropinirole produced the highest incidence rates of dyskinesia side effects, whereas pramipexole was significantly higher in terms of patients hallucination. In addition, the SUCRA values of all the drugs showed that the incidence of adverse reaction of pergolide was relatively high (nausea: 83.5%; hallucination: 79.8%); for dyskinesia and somnolence, the incidence of ropinirole was higher (dyskinesia: 80.5%; somnolence: 69.4%); the incidence of adverse reaction of piribedil was higher on PD in terms of dizziness (67.0%); and the incidence of bromocriptine was relatively high in terms of constipation (62.3%). Conclusions: This mixed treatment comparison showed that the drugs ropinirole, bromocriptine, and piribedil produced the highest incidence rates of nausea, dyskinesia, hallucination, dizziness, constipation, and somnolence symptoms. Thus, we conclude that as these three drugs produced the most frequent symptoms, they are not recommended for the treatment of patients with Parkinson s disease. KEYWORDS adverse events, bayesian network model, Parkinson s disease, randomized controlled trials, surface under the cumulative ranking curves The first two authors contributed equally to this work. CNS Neurosci Ther. 2017;23: wileyonlinelibrary.com/journal/cns 2017 John Wiley & Sons Ltd 827

2 828 1 INTRODUCTION Parkinson s disease (PD) is a long- term degenerative disease of the central nervous system that mainly effects the motor nervous system. 1 It is classified as a neurodegenerative disease in which the degeneration of dopaminergic neurons in substantia nigra results in the depletion of striatum dopamine. 2 Early symptoms of PD include shaking, rigidity, difficulty in walking, and decrease in range of movements, whereas later symptoms usually involve thinking and behavioral changes as well as dementia. 3 Typical clinical manifestations of PD include resting tremors, increased muscle tension, and the lost selfcontrol of extrapyramidal motor function when the degeneration of dopaminergic neurons in substantia nigra is more than 80%. 4 Statistics show that the incidence of PD is slightly higher in male than females and it seriously endangers the health of the elderly, causing memory loss, personality changes, urinary and fecal incontinence, dementia, loss of self- care ability, and affecting longevity. 5 The current reported incidence rate for PD for all age groups ranges between 1.5 and 22 per people a year, which becomes a heavy burden for the family and society. 6 Currently, the exact cause of PD remains elusive, but it is believed to involve both environmental and genetic factors, as shown by family tree evidences. 7 The motor system symptoms that are seen in patients with PD are a result of the death of cells in the substantia nigra, a region of the midbrain. The death in cells results in a decreased response to dopamine in the central nervous system. Currently, research evidences have centralized around the hypothesis that the build- up of proteins called Lewy bodies in the neurons is the potential cause for neuronal death. 7 As the pathogenesis of PD is very complex and unclear, surgical intervention and medical therapy remains the mainstay for PD. 8 L- DOPA is a drug that is mainly used in the treatment for most patients with PD, but due to its side effects, other drugs have been produced using L- DOPA as the parent molecule. The drugs for PD mainly include ergot derivatives of bromocriptine and pergolide which are brain dopamine (DA) receptor agonists. The onset of motor complications, which resulted from the peripheral and central degree of fluctuations of levodopa (LD) and of dopamine, characterized the progression of PD. 9 These drugs can directly stimulate DA receptors in the postsynaptic membrane to overcome the motor complications caused by levodopa 10 ; nonergot DA receptor agonists such as piribedil, pramipexole, rotigotine, ropinirole, apomorphine, and sumanirole 11,12 ; monoamine oxidase (MAO) inhibitor of rasagiline can increase DA mass fraction and protect the DA neurons by preventing MAO- B from dissolving DA 13 ; catechol- O- methyl transferase (COMT) inhibitor of entacapone is an adjunct drug of levodopa that is able to reduce the metabolism of levodopa into 3- oxo methyldopa to increase the mass fraction of dopamine in brain 14 ; levodopa is DA synthetic precursor and decarboxylated into DA by L- amino acid decarboxylase after entering into the brain through blood- brain barrier and being uptaken by DA neurons. 15 Currently, there are limited comprehensive studies to assess the incidences of adverse reactions produced by the various drugs used to treat patients with PD. In this mixed treatment comparison, we comprehensively research related randomized controlled trials of 11 drugs that are currently being used to treat patients with PD. Our aim was to compare the incidences of different adverse effects produce by these drugs during PD treatment. 2 MATERIALS AND METHODS 2.1 Literature search The literature that was used in this analysis was obtained from PubMed, EMBASE, and Cochrane Library which were searched by computer from the inception of each database up until December A manual search was also performed for the reference lists. The search was conducted using keywords combined with free words, and the index words mainly included Parkinson s disease, drug therapy/ medication, adverse events, and randomized controlled trial (RCT). 2.2 Inclusion and exclusion criteria The inclusion criteria of the selected literature included the following: (i) study design: RCT; (ii) interventions: placebo, ropinirole, rasagiline, rotigotine, entacapone, apomorphine, pramipexole, sumanirole, bromocriptine, piribedil, pergolide, and levodopa; (iii) patients diagnosed with PD that were over 50 years old; (iv) literatures that evaluated the adverse effects of different drugs on patients with PD. The exclusion criteria included the following: (i) PD patients who receive surgical treatment; (ii) PD patients with mental disorders; (iii) PD patients with a history of epilepsy or convulsions; (iv) PD patients with orthostatic hypotension; (v) PD patients who previously received dopamine receptor agonists or antipsychotic drug treatment; (vi) PD patients with clinically relevant hepatic, renal, or cardiac disorders; (vii) studies with insufficient data; (viii) non- RCTs; (ix) duplicated publications; (x) conference reports, system evaluation, or the summary article; (xi) non- English literatures. 2.3 Data extraction and quality assessment Selected data that were used in this investigation included those that were independently extracted by two researchers according to a unified data collection form. If there were disputes, a third researcher would be consulted to reach a consensus. Cochrane Collaboration s tool was implemented to assess risk of bias in the randomized controlled trials. 16 Cochrane Collaboration s tool included 6 domains that are known as: random assignment, allocation concealment, blinding, loss outcome data, choosing the outcome reports, and other biases. Each domain was judged as either yes, no, or unclear to produce a bias value of low, high, or unclear risk. Studies that less than or equal to one domain that was determined as unclear or no were categorized as having a low risk of bias. Studies with four or more domains that were deemed unclear or no were categorized as having a high risk of bias. The study with two or three domains deemed unclear or no was categorized as having a moderate risk of bias. 17 Quality assessment and publication bias investigation were carried out using Review Manager 5 (RevMan 5.2.3, Cochrane Collaboration, Oxford, UK).

3 Statistical method Traditional direct comparison for studies which directly compared different treatment arms was carried out. The data were presented with pooled estimates of odds ratios (ORs) with 95% confidence intervals (CIs) of adverse events on Parkinson s disease. Heterogeneity among studies was tested by chi- square test and I 2 test. 18 R software was used to draw a network diagram, in which each node represented an interventional measure. The size of each node represents sample size, and the thickness of line between nodes represents the number of included studies. Different interventional methods were compared using Bayesian network model. Each analysis was based on noninformative prior for effective sizes and precision. Convergence and lack of auto correlation were checked and confirmed after four chains and a simulation burn- in phase. Finally, we derived direct probability statements from an additional simulation phase. 19 The study used the nodesplitting method to evaluate the consistency of direct evidence and indirect evidence. We calculated the probability and effectiveness of each interventional treatment method as well as their safeness based on a Bayesian approach using probability values summarized as surface under the cumulative ranking curve (SUCRA) to interpret ORs. The larger the SUCRA value, the better form of the intervention. 20,21 R (V.3.2.1) package gemtc (V.0.6) and the Markov chain Monte Carlo engine Open BUGS (V.3.4.0) were used to perform all computations. 3 RESULTS 3.1 Baseline characteristics of included literatures We retrieved 1402 related literatures in total, among which 403 repeated literatures, 227 letters or reviews, and 190 non- English literatures were discarded. In the remaining 582 literatures, 231 were nonhuman literatures, 147 literatures had no relations with PD, 178 literatures having no relevance with drug therapy, and two literatures that were without complete data were also eliminated. Results of our study that was performed for 24 randomized Included Eligibility Screening Iden fica on Articles identified through electronic database searching (N = 1401) Articles reviewed for duplicates (N = 403) Articles after duplicates removed (N = 999) Full-text articles assessed for eligibility (N = 582) Studies included in qualitative synthesis (N = 26) Studies included in quantitative synthesis (meta-analysis) (N = 24) Additional articles identified through a manual search (N = 1) Studies were excluded, due to: (N = 227) Letters, reviews, meta-analysis (N = 190) Not English studies Studies were excluded, due to: (N = 231) Not human studies (N = 147) Not relevant to Parkinson s disease (N = 178) Not relevant to drugs therapy FIGURE 1 Screening flowchart of included literatures [Colour figure can be viewed at wileyonlinelibrary.com]

4 830 TABLE 1 The baseline characteristics of included studies Treatments Sample size Gender (M/F) Age (y) First author Year Country D1 D2 D3 Total D1 D2 D3 D1 D2 D3 D1 D2 D3 Nomoto M 2014 Japan A D /42 34/ ± ± Nicholas AP 2014 USA A D /34 79/ ± ± Watts RL 2010 USA B L /44 74/ ± ± Rascol O 2010 France A F NR NR - NR NR - Singer C 2007 USA A B H /80 128/74 129/ ± ± ± 0.8 Poewe WH 2007 Austria A D G /29 132/69 112/ ± ± ± 9.7 Mizuno Y- a 2007 Japan A E /53 41/ ± ± Mizuno Y- b 2007 Japan A B /66 53/ ± ± Jankovic J 2007 USA A D /38 123/ ± ± Giladi N 2007 Israel A B D /50 137/92 118/ Barone P 2007 Italy A B H / / / Castro- Caldas A 2006 Portugal I J /96 117/ ± ± Reichmann H 2005 Germany A E /39 94/ ± ± Rascol O 2005 France A C E /97 154/77 139/ ± ± ± 9.4 Ziegler M 2003 Germany A J /26 40/ ± ± Wong KS 2003 China A G /11 48/ ± ± Navan P 2003 England A G K /4 7/3 6/4 70 (62-78) 66 (55-80) 71 (54-80) Im JH 2003 Korea B I /16 20/19 - NR NR - Fenelon G 2003 Spain A E /25 63/ ± ± Brooks DJ 2003 England A E /17 69/ ± ± Pogarell O 2002 Germany A G /9 30/ ± ± Poewe WH 2002 Austria A E /54 79/ ± ± Brunt ER 2002 England B I /52 44/ Rascol O 2000 France B L /66 52/ ± ± D, drug; M, male; F, female; A, Placebo; B, Ropinirole; C, Rasagiline; D, Rotigotine; E, Entacapone; F,Apomorphine; G,Pramipexole; H, Sumanirole; I, Bromocriptine; J, Piribedil; K, Pergolide; L, ; NR, not reported.

5 831 FIGURE 2 Cochrane system bias evaluations of included literatures [Colour figure can be viewed at wileyonlinelibrary. com] controlled trials are shown in 10,22-44 (Figure 1). The study included 6911 cases of PD patients, and most of them were treated by placebo. The included literatures in the study were published from the year 2000 to In the 24 randomized controlled trials, 19 of the trials were of Caucasian ethnicity and the other five trials were of Asian ethnicity; 18 of the 24 trials were two- arm trials and the remaining six trials were three- arm trials. The baseline characteristics of included literatures are shown in Table 1, and Cochrane bias evaluation is shown in Figure Direct comparison results As shown in Table 2, direct comparison of the adverse effects of all the drugs used in the treatment of PD found that the incidence for nausea was higher in patients who took ropinirole, rotigotine, entacapone, and sumanirole compared to the placebo (OR = 0.44, 95% CI = ; OR = 0.51, 95% CI = ; OR = 0.51, 95% CI = ; OR = 0.43, 95% CI = , respectively) whereby the incidence of ropinirole was relatively higher than bromocriptine (OR = 2.31, 95% CI = ). The incidences rates of dyskinesia were much higher in patients who took ropinirole, rotigotine, pramipexole, sumanirole, and pergolide compared to placebo (OR = 0.30, 95% CI = ; OR = 0.44, 95% CI = ; OR = 0.18, 95% CI = ; OR = 0.37, 95% CI = ; OR = 0.30, 95% CI = , respectively), whereas compared with levodopa, ropinirole presented with higher incidence of dyskinesia on PD (OR = 3.55, 95% CI = ). The incidences of hallucination in patients taking ropinirole, rotigotine, pramipexole, and sumanirole were higher than that of those who took the placebo (OR = 0.38, 95% CI = ; OR = 0.23, 95% CI = ; OR = 0.17, 95% CI = ; OR = 0.32, 95% CI = , respectively) whereby the efficacy of bromocriptine was inferior to piribedil (OR = 0.33, 95% CI = ). The onset of dizziness was less apparent in patients taking of placebo compared to that of sumanirole (OR = 0.41, 95% CI = ). The incidence of ropinirole was lower than that of pergolide in terms of constipation (OR = 0.28, 95% CI = ). The incidence somnolence was lower in patients who took ropinirole compared to those who took sumanirole (OR = 1.75, 95% CI = ; Table 3). 3.3 The evidence of network relationship Among the 24 included studies, majority of the PD patients took placebo and least patients took pergolide among the above eleven drugs. The direct pairwise researches were placebo vs entacapone (Figure 3). 3.4 Nonconsistency test We used the node- splitting method to perform a nonconsistency check for the results of nausea, dyskinesia, hallucination, dizziness, constipation, and somnolence and found that the direct evidences were consistent with the indirect evidences so that we should use consistency model (P > 0.05; Table 4). 3.5 Indirect comparison results Indirect comparison results showed the incidences of adverse reactions of ropinirole, rotigotine, entacapone, and sumanirole were obviously higher than that of placebo (OR = 2.48, 95% CI = ; OR = 2.20, 95% CI = ; OR = 2.25, 95% CI = ; OR = 2.12, 95% CI = , respectively). As for dyskinesia, the incidence rate of ropinirole was obviously higher than that of the placebo (OR = 3.99, 95% CI = ). Additionally, patients who took pramipexole had higher incidence rates of hallucinations compared to those who took the placebo (OR = 7.56, 95% CI = ; Appendix A1; Figure 4). We also found that in terms of dizziness, constipation, and somnolence, the incidence of these symptoms had no significant differences in all the investigating drugs (Appendix A2). 3.6 Cumulative probability of sorting In terms of nausea and hallucination, SUCRA values of all the drugs tested indicated that the incidence of adverse reactions of pergolide was relatively higher (nausea: 83.5%; hallucination: 79.8%), whereas the incidence of placebo was lower (nausea: 21.0%; hallucination: 16.7%). In terms of dyskinesia and somnolence, the incidence of ropinirole was high (dyskinesia: 80.5%; somnolence: 69.4%), and the incidence of placebo was low (dyskinesia: 20.2%; somnolence: 23.4%). In terms of dizziness, the incidence of piribedil was higher (67.0%), while the incidence of placebo was lower (25.2%). The incidence

6 832 TABLE 2 Direct comparison results of nausea, dyskinesia and hallucination Events/Total Pairwise meta- analysis Included studies Nausea Comparisons Drug1 Drug2 OR (95%CI) I 2 P h 4 studies A vs B 77/ / ( ) 73.4% A vs C 10/229 8/ ( ) NA NA 5 studies A vs D 56/ / ( ) 60.0% studies A vs E 22/613 60/ ( ) 46.5% A vs F 1/30 1/ ( ) NA NA 3 studies A vs G 14/151 33/ ( ) 0.0% A vs H 47/517 97/ ( ) 0.0% A vs K 0/10 3/ ( ) NA NA B vs D 36/228 29/ ( ) NA NA B vs H 114/512 97/ ( ) 89.1% B vs I 40/131 12/ ( ) NA NA B vs L 113/283 60/ ( ) 42.9% C vs E 8/231 13/ ( ) NA NA D vs G 35/204 26/ ( ) NA NA G vs K 0/10 3/ ( ) NA NA I vs J 40/215 36/ ( ) NA NA Dyskinesia A vs B 11/436 36/ ( ) 38.9% A vs C 9/229 12/ ( ) NA NA 3 studies A vs D 13/296 40/ ( ) 0.0% studies A vs E 40/447 74/ ( ) 61.1% A vs G 3/111 32/ ( ) 0.0% A vs H 9/314 23/ ( ) NA NA A vs K 0/10 1/ ( ) NA NA B vs H 22/310 23/ ( ) NA NA B vs I 24/168 11/ ( ) 0.0% B vs L 23/89 16/ ( ) NA NA C vs E 12/231 14/ ( ) NA NA D vs G 24/204 31/ ( ) NA NA G vs K 1/10 1/ ( ) NA NA I vs J 10/215 6/ ( ) NA NA Hallucination A vs B 8/436 22/ ( ) 43.7% A vs C 3/229 5/ ( ) NA NA A vs D 3/188 18/ ( ) 0.0% studies A vs E 13/570 28/ ( ) 55.0% A vs G 2/111 17/ ( ) 0.0% A vs H 6/314 18/ ( ) NA NA A vs K 1/10 4/ ( ) NA NA B vs H 10/310 18/ ( ) NA NA B vs I 11/168 3/ ( ) 0.0% C vs E 5/231 8/ ( ) NA NA D vs G 10/204 14/ ( ) NA NA G vs K 3/10 4/ ( ) NA NA I vs J 6/215 17/ ( ) NA NA OR, odds ratio; CI, confidence intervals; NA, not available; A, Placebo; B, Ropinirole; C, Rasagiline; D, Rotigotine; E, Entacapone; F, Apomorphine; G, Pramipexole; H, Sumanirole; I, Bromocriptine; J, Piribedil; K, Pergolide; L,. Bolded numbers represent the differences are of significance.

7 833 TABLE 3 Direct comparison results of dizziness, constipation and somnolence Events/Total Pairwise meta- analysis Included studies Dizziness Comparisons Drug1 Drug2 OR (95% CI) I 2 P h 4 studies A vs B 50/ / ( ) 73.4% A vs C 4/229 6/ ( ) NA NA 4 studies A vs D 43/409 71/ ( ) 71.4% A vs E 28/306 26/ ( ) 0.0% A vs F 1/30 1/ ( ) NA NA A vs G 7/50 9/ ( ) 0.0% A vs H 30/517 68/ ( ) 21.4% A vs J 1/54 2/ ( ) NA NA A vs K 1/10 1/ ( ) NA NA B vs D 17/228 14/ ( ) NA NA B vs H 78/512 68/ ( ) 49.1% B vs I 31/168 24/ ( ) 0.0% B vs L 39/193 51/ ( ) 13.2% C vs E 6/231 6/ ( ) NA NA G vs K 1/10 1/ ( ) NA NA I vs J 30/215 31/ ( ) NA NA Constipation A vs B 11/321 22/ ( ) 0.0% A vs C 1/229 3/ ( ) NA NA 4 studies A vs D 17/409 31/ ( ) 51.9% studies A vs E 30/620 50/ ( ) 80.1% A vs G 3/10 2/ ( ) NA NA A vs H 7/203 14/ ( ) NA NA A vs K 3/10 2/ ( ) NA NA B vs D 9/228 7/ ( ) NA NA B vs H 13/202 14/ ( ) NA NA B vs I 1/37 2/ ( ) NA NA B vs K 7/141 14/ ( ) 36.7% B vs L 11/89 17/ ( ) NA NA C vs E 3/231 4/ ( ) NA NA I vs J 22/215 14/ ( ) NA NA Somnolence 4 studies A vs B 61/ / ( ) 85.8% A vs C 2/229 3/ ( ) NA NA 5 studies A vs D 57/ / ( ) 72.8% studies A vs E 15/420 15/ ( ) 22.4% A vs G 8/101 24/ ( ) NA NA 3 studies A vs H 59/827 96/ ( ) 72.8% B vs D 28/228 23/ ( ) NA NA B vs H 63/202 42/ ( ) NA NA B vs L 30/193 55/ ( ) 78.9% C vs E 3/231 3/ ( ) NA NA D vs G 25/204 24/ ( ) NA NA OR, odds ratio; CI, confidence intervals; NA,not available; A, Placebo; B, Ropinirole; C, Rasagiline; D, Rotigotine; E, Entacapone; F, Apomorphine; G,Pramipexole; H, Sumanirole; I, Bromocriptine; J, Piribedil; K, Pergolide; L,, Bolded numbers represent the differences are of significance.

8 834 (A) Nausea Placebo (B) Dyskinesia Placebo 4 studies Pergolide Ropinirole Rasagiline Pergolide Ropinirole Rasagiline 3 studies 5 studies Piribedil 5 studies Rotigotine Piribedil 6 studies Rotigotine Bromocriptine 3 studies Apomorphine Entacapone Bromocriptine Entacapone Sumanirole Pramipexole Sumanirole Pramipexole (C) Hallucination (D) Dizziness Placebo Placebo 4 studies Pergolide Ropinirole Ropinirole Piribedil Rasagiline Pergolide Rasagiline 4 studies Bromocriptine 5 studies Rotigotine Piribedil Rotigotine Bromocriptine Entacapone Sumanirole Pramipexole Entacapone Sumanirole Pramipexole Apomorphine (E) Constipation (F) Somnolence Placebo Placebo Ropinirole 4 studies Ropinirole Pergolide Rasagiline 3 studies 4 studies 5 studies Piribedil 5 studies Sumanirole 3 studies Rasagiline Rotigotine Bromocriptine Pramipexole Pramipexole Entacapone Rotigotine Sumanirole Entacapone FIGURE 3 Network diagram showing the improvement of symptoms in the symptoms of nausea, dyskinesia, hallucination, dizziness, constipation, and somnolence in the investigated drugs. (Note: dashed line, no direct contrast between the two interventions; solid line, direct comparison between the two interventions; the size of circle indicates the scale of sample, the larger the circle is, the larger the scale of sample; the thickness of solid line indicates the number of direct comparison, the thicker the line, the more the number of comparison) [Colour figure can be viewed at wileyonlinelibrary.com]

9 835 TABLE 4 OR values and P values of direct and indirect pairwise comparisons of seven treatment modalities under six endpoint outcomes Direct OR values Indirect OR values P values Na Dy Ha Di Co So Na Dy Ha Di Co So Na Dy Ha Di Co So Pairwise comparisons B vs A 0.80 NR NR NR 0.90 NR NR NR NR NR NR J vs A NR NR NR 2.10 NR NR NR NR NR 2.20 NR NR NR NR NR NR NR K vs A NR NR NR NR 0.56 NR NR NR NR NR 9.00 NR NR NR NR NR NR D vs B NR NR NR NR NR NR NR NR NR I vs B NR NR NR 1.10 NR NR NR NR NR 1.10 NR NR NR NR NR NR NR K vs B NR NR NR NR 5.10 NR NR NR NR NR 0.31 NR NR NR NR NR NR G vs D NR NR NR NR NR NR NR NR NR J vs I NR NR NR 1.10 NR NR NR NR NR 1.10 NR NR NR NR NR NR NR Na, nausea; Dy, dyskinesia; Ha, hallucination; Di, dizziness; Co, constipation; So, somnolence; OR, odds ratio; NR, not report; A, Placebo; B, Ropinirole; C, Rasagiline; D, Rotigotine; E, Entacapone; F, Apomorphine; G, Pramipexole; H, Sumanirole; I, Bromocriptine; J, Piribedil; K, Pergolide; L, ; NR, not reported. (A) Nausea Comparison Odds Ratio (95% CI) B vs A 2.48 (1.40, 4.28) C vs A 1.03 (0.30, 3.48) D vs A 2.20 (1.27, 3.74) E vs A 2.25 (1.19, 4.26) F vs A 1.01 (0.03, 32.75) G vs A 1.60 (0.66, 3.75) H vs A 2.12 (1.02, 4.35) I vs A 1.07 (0.26, 3.92) J vs A 0.94 (0.16, 5.38) K vs A 5.88 (0.61, 72.92) L vs A 1.96 (0.69, 5.12) (B) Dyskinesia Comparison Odds Ratio (95% CI) B vs A 3.99 (1.22, 15.05) C vs A 1.29 (0.30, 6.07) D vs A 2.26 (0.79, 6.40) E vs A 1.55 (0.79, 3.39) F vs A 3.28 (0.79, 12.54) G vs A 3.50 (0.81, 16.27) H vs A 2.28 (0.39, 13.71) I vs A 1.32 (0.11, 17.92) J vs A 1.57 (0.03, 33.53) K vs A 1.14 (0.15, 9.09) (C) Hallucination Comparison Odds Ratio (95% CI) B vs A 3.39 (0.63, 19.91) C vs A 1.15 (0.12, 11.66) D vs A 5.20 (0.82, 34.90) E vs A 1.68 (0.48, 5.38) F vs A 7.56 (1.01, 61.27) G vs A 4.41 (0.51, 42.17) H vs A 1.24 (0.08, 21.77) I vs A 3.90 (0.12, ) J vs A (0.60, ) FIGURE 4 The relative relationship forest diagram showing the improvement of nausea, dyskinesia, and hallucination in the 11 drugs. (A = placebo; B = ropinirole; C = rasagiline; D = rotigotine; E = entacapone; F = apomorphine; G = pramipexole; H = sumanirole; I = bromocriptine; J = piribedil; K = pergolide; L = levodopa) (Note: all comparisons in the figure were based on placebo as a control, 95% of the range of confidence intervals located left or right side of 1 was treated as indicating significant differences; such as the results of B vs A, odds ratio = 2.48 (OR > 1) and 95% CI = (the range of it located right of 1), this means compared with A, B has relatively high incidence of adverse reactions, and vice versa) [Colour figure can be viewed at wileyonlinelibrary.com] of bromocriptine was high (62.3%), while that of placebo was low (36.6%) in terms of constipation (Table 5). However, the results involved in pergolide are based on a small number of samples, so they need further validation.

10 836 TABLE 5 SUCRA values of twelve treatment modalities under 6 endpoint outcomes SUCRA values Treatments Nausea Dyskinesia Hallucination Dizziness Constipation Somnolence A B C D E F NR NR NR NR G H I NR J NR K NR L NR SUCRA, surface under the cumulative ranking curves; NR, not report; A, Placebo; B, Ropinirole; C, Rasagiline; D, Rotigotine; E, Entacapone; F, Apomorphine; G, Pramipexole; H, Sumanirole; I, Bromocriptine; J, Piribedil; K, Pergolide; L, ; NR, Not reported, Bold font indictaes the SUCRA is relatively higher when compared with other interventions. 4 DISCUSSION PD is a chronic, gradually progressive disease that results from striatal dysfunction caused by degeneration of dopaminergic neurons in the substantia nigra. Drugs such as dopamine agonists have contributed to improving patient management suffering from PD. Although an improvement in the general conditions has been clearly seen, some detrimental side effects are also produced during the same time. With the purpose of offering a better quality of life of patients and instructions at the time of choosing the most appropriate treatment, this study compares eleven dopamine agonists use for PD treatment and confirmed that the incidences of adverse reaction of pergolide, ropinirole, piribedil, and bromocriptine were the highest through direct comparison and a mixed treatment comparison. The direct comparison results showed that the incidences of adverse reaction of ropinirole, piribedil, and bromocriptine were higher than other drugs, in the symptoms of somnolence, hallucination, dyskinesia, nausea, dizziness, and constipation. Due to the high affinities for the dopamine D2 and D3 receptors, dopamine agonist therapy may result in impulse control disorder through D3 receptors, and the dopamine agonists would cause side effects while acting anti- Parkinson s functions. 45 Ropinirole, as a nonergot dopamine receptor agonist, takes up an important position in the management of PD. 46 However, as shown in this study, it does produce a significant number of side effects such as dyskinesia and somnolence. A mixed treatment comparison by Jaime Kulisevsky and Javier Pagonabarraga also showed that the incidence of adverse reactions for ropinirole was similar to those found in the present study. Both studies showed high incidences of several adverse reactions induced by ropinirole such as dyskinesia, somnolence. 47 Previous studies have also supported out findings that with the results of high incidence of si milar adverse reactions in PD patients treated with ropinirole. 29,48 In the present study, we found that piribedil produced the highest incidence of dizziness symptoms. Piribedil is a nonergotaminic dopamine D2/3/4 receptor agonist and alpha 2A/B/C blocker that is used for a monotherapy and add- on to L- DOPA form of treatment when treating PD patients. 49 The relatively strong anticholinergic properties of piribedil may be underlying molecular the cause that results in high incidence of dizziness. When piribedil is being used in a long- term manner, potential significant anticholinergic side effects (eg, hallucinations, sicca symptoms, tachycardia, or urinary difficulty) may develop as a result. 50 Piribedil may worsen levodopa- associated dyskinesia and induce dyskinesia in levodopa- naive marmosets just like any other dopamine agonist. 51 In addition to motor dysfunctions, nonmotor dysfunctions such as neuropsychiatric symptoms, sleep disorders, sensory symptoms, and autonomic dysfunctions also affect patients suffering from PD. 52 Constipation is one of these problems and was identified with high onset in the present study, which was induced by bromocriptine. Although there are not enough up- to- date studies of bromocriptine in the management of PD, results of a former study showed high incidence of adverse reactions in PD patients treated with bromocriptine and were considered drug- related. 53 Several limitations were present during the interpretations of our results in this investigation. When considering the equity of interventions, we are unable to perform a cluster diagram and directly show results. Additionally, we only found one literature that investigates the side effects of pergolide. There was a lack of sample size and insufficiency of data for pergolide to help evaluate its results in the study. Therefore, to ensure the reliability of the conclusion, we do not refer to pergolide in the conclusion. Despite out limitations, we managed to obtain a large subject sample size and the results of

11 837 multiple comparisons were unified, which produced significant and accurate results. In conclusion, the results of the present study showed that the incidences of adverse reactions produced by ropinirole, piribedil, and bromocriptine were the highest among the 11 drugs, thereby affect the of patients quality of life over the course of treatment. Therefore, we hope that our analysis will be clinically useful in the selection of drugs for the treatment of PD. The aforementioned drugs with the highest incidence rates of side effects should be heavily considered and are not recommended for treatment of PD. In addition to current forms of treatment, we hope that our results can produce useful information for further development of new drugs to treat PD based on the natures of each drug. ACKNOWLEDGMENTS We would like to acknowledge the helpful comments on this article received from our reviewers. CONFLICT OF INTERESTS The authors declare no conflict of interest. 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13 839 APPENDIX A1 ODDS RATIOS AND 95% CONFIDENCE INTERVALS OF ELEVEN DRUGS IN THE TREATMENT OF PARKINSON IN TERMS OF NAUSEA, DYSKINESIA, AND HALLUCINATION. Nausea Placebo 2.48 (1.40, 4.28) 1.03 (0.30, 3.48) 2.20 (1.27, 3.74) 2.25 (1.19, 4.26) 1.01 (0.03, 32.75) 1.60 (0.66, 3.75) 2.12 (1.02, 4.35) 1.07 (0.26, 3.92) 0.94 (0.16, 5.38) 5.88 (0.61, 72.92) 1.96 (0.69, 5.12) 0.40 (0.23, 0.72) Ropinirole 0.41 (0.11, 1.59) 0.88 (0.44, 1.80) 0.91 (0.38, 2.15) 0.41 (0.01, 13.54) 0.64 (0.24, 1.76) 0.85 (0.41, 1.80) 0.43 (0.12, 1.45) 0.38 (0.07, 1.96) 2.39 (0.23, 30.06) 0.78 (0.33, 1.76) 0.97 (0.29, 3.39) 2.45 (0.63, 9.51) Rasagiline 2.13 (0.57, 8.35) 2.19 (0.66, 7.85) 1.00 (0.02, 37.53) 1.55 (0.35, 7.03) 2.06 (0.50, 8.68) 1.04 (0.16, 6.41) 0.93 (0.10, 7.97) 5.87 (0.45, 91.67) 1.90 (0.38, 9.12) 0.46 (0.27, 0.79) 1.13 (0.56, 2.29) 0.47 (0.12, 1.74) Rotigotine 1.03 (0.45, 2.38) 0.46 (0.01, 15.18) 0.73 (0.30, 1.75) 0.96 (0.41, 2.36) 0.49 (0.11, 1.93) 0.43 (0.07, 2.61) 2.70 (0.27, 34.06) 0.89 (0.29, 2.61) 0.44 (0.23, 0.84) 1.10 (0.46, 2.61) 0.46 (0.13, 1.52) 0.97 (0.42, 2.21) Entacapone 0.45 (0.01, 15.13) 0.70 (0.24, 2.04) 0.94 (0.35, 2.41) 0.48 (0.10, 2.03) 0.42 (0.06, 2.73) 2.64 (0.25, 34.62) 0.87 (0.25, 2.74) 0.99 (0.03, 39.19) 2.45 (0.07, 99.40) 1.00 (0.03, 46.04) 2.18 (0.07, 90.31) 2.21 (0.07, 87.63) Apomorphine 1.59 (0.05, 66.97) 2.04 (0.06, 86.77) 1.03 (0.03, 54.07) 0.93 (0.02, 51.53) 5.88 (0.10, ) 1.89 (0.05, 85.64) 0.63 (0.27, 1.52) 1.55 (0.57, 4.18) 0.65 (0.14, 2.83) 1.37 (0.57, 3.39) 1.42 (0.49, 4.23) 0.63 (0.01, 21.63) Pramipexole 1.32 (0.42, 4.07) 0.67 (0.13, 3.11) 0.59 (0.08, 4.10) 3.71 (0.38, 44.49) 1.22 (0.32, 4.35) 0.47 (0.23, 0.98) 1.18 (0.56, 2.43) 0.49 (0.12, 2.01) 1.04 (0.42, 2.46) 1.06 (0.41, 2.86) 0.49 (0.01, 17.31) 0.76 (0.25, 2.38) Sumanirole 0.50 (0.12, 2.04) 0.45 (0.07, 2.69) 2.78 (0.27, 38.79) 0.92 (0.29, 2.71) 0.94 (0.26, 3.80) 2.33 (0.69, 8.29) 0.96 (0.16, 6.17) 2.06 (0.52, 8.87) 2.10 (0.49, 9.89) 0.97 (0.02, 36.89) 1.49 (0.32, 7.87) 1.99 (0.49, 8.52) Bromocriptine 0.90 (0.30, 2.66) 5.64 (0.41, 96.73) 1.84 (0.41, 8.42) 1.06 (0.19, 6.26) 2.63 (0.51, 13.78) 1.07 (0.13, 9.60) 2.32 (0.38, 14.61) 2.36 (0.37, 16.18) 1.08 (0.02, 48.46) 1.69 (0.24, 12.60) 2.22 (0.37, 14.18) 1.12 (0.38, 3.33) Piribedil 6.35 (0.36, ) 2.03 (0.32, 13.20) 0.17 (0.01, 1.65) 0.42 (0.03, 4.31) 0.17 (0.01, 2.20) 0.37 (0.03, 3.68) 0.38 (0.03, 4.00) 0.17 (0.00, 10.28) 0.27 (0.02, 2.63) 0.36 (0.03, 3.73) 0.18 (0.01, 2.44) 0.16 (0.01, 2.79) Pergolide 0.33 (0.02, 3.92) 0.51 (0.20, 1.45) 1.28 (0.57, 3.01) 0.53 (0.11, 2.63) 1.13 (0.38, 3.40) 1.15 (0.36, 3.97) 0.53 (0.01, 19.28) 0.82 (0.23, 3.12) 1.08 (0.37, 3.43) 0.54 (0.12, 2.41) 0.49 (0.08, 3.14) 3.06 (0.26, 45.72) Dyskinesia Placebo 3.99 (1.22, 15.05) 1.29 (0.30, 6.07) 2.26 (0.79, 6.40) 1.55 (0.79, 3.39) 3.28 (0.79, 12.54) 3.50 (0.81, 16.27) 2.28 (0.39, 13.71) 1.32 (0.11, 17.92) 1.57 (0.03, 33.53) 1.14 (0.15, 9.09) 0.25 (0.07, 0.82) Ropinirole 0.32 (0.04, 2.22) 0.56 (0.11, 2.67) 0.39 (0.09, 1.58) 0.82 (0.11, 4.82) 0.89 (0.20, 3.62) 0.56 (0.16, 2.00) 0.33 (0.04, 2.94) 0.38 (0.01, 9.52) 0.28 (0.06, 1.36) 0.77 (0.16, 3.34) 3.11 (0.45, 22.34) Rasagiline 1.73 (0.27, 10.34) 1.20 (0.28, 5.43) 2.54 (0.32, 18.20) 2.71 (0.33, 24.20) 1.77 (0.16, 17.82) 1.01 (0.05, 19.60) 1.17 (0.02, 36.58) 0.87 (0.07, 11.03) 0.44 (0.16, 1.26) 1.80 (0.37, 9.47) 0.58 (0.10, 3.69) Rotigotine 0.69 (0.20, 2.60) 1.47 (0.37, 5.46) 1.55 (0.26, 10.23) 1.02 (0.13, 8.62) 0.60 (0.04, 9.54) 0.68 (0.01, 15.81) 0.50 (0.05, 5.09) (Continues)

14 840 APPENDIX A1 (Continued) 0.64 (0.29, 1.26) 2.56 (0.63, 11.31) 0.83 (0.18, 3.59) 1.45 (0.38, 5.04) Entacapone 2.13 (0.41, 9.55) 2.25 (0.42, 12.17) 1.46 (0.22, 10.07) 0.85 (0.06, 12.41) 0.99 (0.02, 22.69) 0.73 (0.09, 6.32) 0.30 (0.08, 1.26) 1.23 (0.21, 8.95) 0.39 (0.05, 3.13) 0.68 (0.18, 2.74) 0.47 (0.10, 2.46) Pramipexole 1.07 (0.14, 8.98) 0.69 (0.07, 7.36) 0.40 (0.03, 7.46) 0.47 (0.01, 9.65) 0.34 (0.03, 4.35) 0.29 (0.06, 1.23) 1.13 (0.28, 5.01) 0.37 (0.04, 3.06) 0.64 (0.10, 3.86) 0.44 (0.08, 2.39) 0.94 (0.11, 7.14) Sumanirole 0.64 (0.10, 4.70) 0.38 (0.03, 5.02) 0.43 (0.01, 13.18) 0.32 (0.04, 2.87) 0.44 (0.07, 2.54) 1.78 (0.50, 6.27) 0.57 (0.06, 6.11) 0.98 (0.12, 7.52) 0.69 (0.10, 4.61) 1.46 (0.14, 13.59) 1.57 (0.21, 10.47) Bromocriptine 0.59 (0.10, 3.41) 0.68 (0.01, 23.10) 0.49 (0.07, 3.83) 0.75 (0.06, 8.78) 3.00 (0.34, 26.78) 0.99 (0.05, 18.44) 1.67 (0.10, 24.25) 1.18 (0.08, 16.10) 2.48 (0.13, 39.20) 2.66 (0.20, 36.51) 1.69 (0.29, 9.95) Piribedil 1.14 (0.01, 61.30) 0.85 (0.06, 12.83) 0.64 (0.03, 34.36) 2.65 (0.11, ) 0.85 (0.03, 57.89) 1.47 (0.06, 81.78) 1.01 (0.04, 57.82) 2.13 (0.10, ) 2.32 (0.08, ) 1.47 (0.04, 95.56) 0.87 (0.02, 81.25) Pergolide 0.75 (0.02, 54.44) 0.88 (0.11, 6.50) 3.55 (0.74, 17.02) 1.15 (0.09, 13.73) 1.99 (0.20, 19.52) 1.37 (0.16, 11.40) 2.92 (0.23, 31.30) 3.13 (0.35, 26.46) 2.02 (0.26, 14.73) 1.18 (0.08, 17.33) 1.33 (0.02, 49.50) Hallucination Placebo 3.39 (0.63, 19.91) 1.15 (0.12, 11.66) 5.20 (0.82, 34.90) 1.68 (0.48, 5.38) 7.56 (1.01, 61.27) 4.41 (0.51, 42.17) 1.24 (0.08, 21.77) 3.90 (0.12, ) (0.60, ) 0.29 (0.05, 1.59) Ropinirole 0.34 (0.02, 5.73) 1.64 (0.12, 19.35) 0.47 (0.05, 3.77) 2.33 (0.15, 32.41) 1.32 (0.15, 11.49) 0.39 (0.05, 3.51) 1.17 (0.06, 28.53) 3.55 (0.10, 80.42) 0.87 (0.09, 8.10) 2.92 (0.17, 51.71) Rasagiline 4.47 (0.23, 77.76) 1.43 (0.14, 11.81) 6.50 (0.31, ) 4.12 (0.16, 88.64) 1.00 (0.03, 39.57) 3.76 (0.05, ) 9.68 (0.24, ) 0.19 (0.03, 1.23) 0.61 (0.05, 8.42) 0.22 (0.01, 4.31) Rotigotine 0.31 (0.03, 2.82) 1.37 (0.19, 11.15) 0.85 (0.05, 17.01) 0.25 (0.01, 7.09) 0.75 (0.01, 47.42) 2.30 (0.10, 41.35) 0.59 (0.19, 2.10) 2.11 (0.27, 18.76) 0.70 (0.08, 6.97) 3.23 (0.35, 31.18) Entacapone 4.73 (0.44, 51.40) 2.62 (0.23, 36.93) 0.75 (0.04, 17.68) 2.31 (0.06, ) 7.10 (0.30, ) 0.13 (0.02, 0.99) 0.43 (0.03, 6.73) 0.15 (0.01, 3.27) 0.73 (0.09, 5.40) 0.21 (0.02, 2.29) Pramipexole 0.60 (0.03, 12.58) 0.17 (0.01, 5.69) 0.53 (0.01, 36.39) 1.56 (0.10, 18.79) 0.23 (0.02, 1.98) 0.76 (0.09, 6.73) 0.24 (0.01, 6.39) 1.18 (0.06, 19.45) 0.38 (0.03, 4.44) 1.67 (0.08, 33.69) Sumanirole 0.27 (0.01, 6.41) 0.89 (0.02, 43.77) 2.53 (0.06, 72.40) 0.81 (0.05, 12.21) 2.56 (0.28, 22.10) 1.00 (0.03, 28.81) 4.02 (0.14, ) 1.33 (0.06, 25.78) 5.81 (0.18, ) 3.72 (0.16, 79.99) Bromocriptine 3.30 (0.32, 32.95) 8.54 (0.13, ) 0.26 (0.01, 8.33) 0.85 (0.04, 17.32) 0.27 (0.00, 18.32) 1.33 (0.02, 67.46) 0.43 (0.01, 17.12) 1.88 (0.03, ) 1.13 (0.02, 50.55) 0.30 (0.03, 3.09) Piribedil 2.89 (0.02, ) 0.09 (0.01, 1.66) 0.28 (0.01, 9.69) 0.10 (0.00, 4.11) 0.43 (0.02, 10.32) 0.14 (0.01, 3.33) 0.64 (0.05, 9.72) 0.40 (0.01, 16.52) 0.12 (0.00, 7.95) 0.35 (0.00, 44.79) Pergolide Bolded numbers represent the differences are of significance.