| |
Received: 10 May 2017    Revised: 7 August 2017    Accepted: 8 August 2017
DOI: 10.1111/cns.12727
ORIGINAL ARTICLE
Adverse effects produced by different drugs used in the
treatment of Parkinson’s disease: A mixed treatment
comparison
Bao-Dong Li1 | Zhen-Yun Bi1 | Jing-Feng Liu1 | Wei-Jun Si1 | Qian-Qian Shi1 |
Li-Peng Xue1 | Jing Bai2
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.
Email: drbaijing_bj@163.com
The first two authors contributed equally to this work.
CNS Neurosci Ther. 2017;23:827–842. © 2017 John Wiley & Sons Ltd |  827
 
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 com-
pare 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 2015. Our analysis combines the evidences of direct comparison and
indirect comparison between various literatures. We evaluated the merging odds ra-
tios (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, rotigo-
tine, entacapone, and sumanirole were obviously higher in terms of nausea compared
to the placebo. Ropinirole produced the highest incidence rates of dyskinesia side ef-
fects, 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, bro-
mocriptine, 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 recom-
mended 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
wileyonlinelibrary.com/journal/cns  
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828       LI et al.
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 degenera-
tion of dopaminergic neurons in substantia nigra results in the deple-
tion 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
3
changes as well as dementia. Typical clinical manifestations of PD
include resting tremors, increased muscle tension, and the lost self-­
control 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 100 000 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,
7
as shown by family tree evidences. 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 hypothe-
sis 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
8
remains the mainstay for PD.
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 com-
plications, which resulted from the peripheral and central degree of
fluctuations of levodopa (LD) and of dopamine, characterized the
9
progression of PD. These drugs can directly stimulate DA receptors
in the postsynaptic membrane to overcome the motor complications
caused by levodopa10; nonergot DA receptor agonists such as piribedil,
pramipexole, rotigotine, ropinirole, apomorphine, and sumanirole11,12;
monoamine oxidase (MAO) inhibitor of rasagiline can increase DA
mass fraction and protect the DA neurons by preventing MAO-­B from
dissolving DA13; 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 brain14; levodopa is DA synthetic precursor
and decarboxylated into DA by L-­amino acid decarboxylase after en-
tering into the brain through blood-­brain barrier and being uptaken
15
by DA neurons. 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 compari-
son, 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
2015. 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, bro-
mocriptine, 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 exclu-
sion criteria included the following: (i) PD patients who receive surgi-
cal treatment; (ii) PD patients with mental disorders; (iii) PD patients
with a history of epilepsy or convulsions; (iv) PD patients with orthos-
tatic 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) stud-
ies 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 uni-
fied 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 con-
trolled 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 assess-
ment and publication bias investigation were carried out using Review
Manager 5 (RevMan 5.2.3, Cochrane Collaboration, Oxford, UK).
LI et al. |
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each interventional treatment method as well as their safeness based

2.4 | Statistical method
Traditional direct comparison for studies which directly compared dif-
ferent 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 I2 test.18 R 3.2.1 software was
used to draw a network diagram, in which each node represented an in-
terventional 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 ef-
fective sizes and precision. Convergence and lack of auto correlation
were checked and confirmed after four chains and a 20 000-­simulation
burn-­in phase. Finally, we derived direct probability statements from
an additional 50 000-­simulation phase.19 The study used the node-­
splitting method to evaluate the consistency of direct evidence and
indirect evidence. We calculated the probability and effectiveness of
Idenficaon
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 elimi-
nated. Results of our study that was performed for 24 randomized

Articles identified through Additional articles identified

electronic database searching through a manual search
(N = 1401) (N = 1)

Articles reviewed for duplicates

(N = 403)
Screening

Articles after duplicates Studies were excluded, due to:

removed (N = 227) Letters, reviews, meta-analysis
(N = 999) (N = 190) Not English studies

Full-text articles assessed Studies were excluded, due to:

for eligibility (N = 231) Not human studies
(N = 147) Not relevant to Parkinson’s disease
Eligibility

(N = 582) (N = 178) Not relevant to drugs therapy

Studies included in
qualitative synthesis
(N = 26)
Included

Studies included in
quantitative synthesis
(meta-analysis)
(N = 24)

F I G U R E   1   Screening flowchart of included literatures [Colour figure can be viewed at wileyonlinelibrary.com]

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830      

T A B L E   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 -­ 172 86 86 -­ 44/42 34/52 -­ 66.8 ± 8.3 67.0 ± 6.8 -­

Nicholas AP 2014 USA A D -­ 215 108 107 -­ 74/34 79/28 -­ 64.8 ± 10.2 64.6 ± 9.0 -­
Watts RL 2010 USA B L -­ 208 104 104 -­ 60/44 74/30 -­ 61.4 ± 7.0 62.1 ± 7.2 -­
Rascol O 2010 France A F -­ 60 30 30 -­ NR NR -­ NR NR -­
Singer C 2007 USA A B H 609 203 202 204 123/80 128/74 129/75 64.8 ± 0.7 65.4 ± 0.8 63.4 ± 0.8
Poewe WH 2007 Austria A D G 501 100 201 200 71/29 132/69 112/88 65.0 ± 10.0 64.3 ± 9.0 63.2 ± 9.7
Mizuno Y-­a 2007 Japan A E -­ 183 95 88 42/53 41/47 -­ 62.7 ± 9.9 62.7 ± 8.7 -­
Mizuno Y-­b 2007 Japan A B -­ 241 120 121 -­ 54/66 53/68 -­ 64.7 ± 9.31 64.9 ± 9.53 -­
Jankovic J 2007 USA A D -­ 277 96 181 -­ 58/38 123/58 -­ 64.5 ± 10.7 62.0 ± 10.3 -­
Giladi N 2007 Israel A B D 561 118 228 215 68/50 137/92 118/97 60.4 61.6 61.1
Barone P 2007 Italy A B H 939 314 310 315 193/121 194/116 187/128 65.1 64.1 64.6
Castro-­Caldas 2006 Portugal I J -­ 425 215 210 -­ 119/96 117/93 -­ 65.1 ± 7.9 65.3 ± 7.6 -­
A
Reichmann H 2005 Germany A E -­ 270 96 174 -­ 57/39 94/80 -­ 66.0 ± 9.0 67.0 ± 8.0 -­
Rascol O 2005 France A C E 687 229 231 227 132/97 154/77 139/88 64.8 ± 8.8 63.9 ± 9.9 63.0 ± 9.4
Ziegler M 2003 Germany A J -­ 115 54 61 -­ 28/26 40/21 -­ 64.8 ± 7.6 63.4 ± 7.3 -­
Wong KS 2003 China A G -­ 150 77 73 -­ 56/11 48/25 -­ 60.94 ± 1.11 58.8 ± 1.28 -­
Navan P 2003 England A G K 30 10 10 10 6/4 7/3 6/4 70 (62-­78) 66 (55-­80) 71 (54-­80)
Im JH 2003 Korea B I -­ 76 37 39 -­ 21/16 20/19 -­ NR NR -­
Fenelon G 2003 Spain A E -­ 162 63 99 -­ 38/25 63/36 -­ 65.0 ± 6.61 63.5 ± 9.96 -­
Brooks DJ 2003 England A E -­ 172 57 115 -­ 40/17 69/46 -­ 64.7 ± 8.5 65.9 ± 8.9 -­
Pogarell O 2002 Germany A G -­ 83 39 44 -­ 30/9 30/14 -­ 65.4 ± 7.1 62.0 ± 10.1 -­
Poewe WH 2002 Austria A E -­ 301 104 197 -­ 50/54 79/118 -­ 61.1 ± 9.9 60.7 ± 9.6 -­
Brunt ER 2002 England B I -­ 206 131 75 -­ 79/52 44/31 -­ 65.5 66.4 -­
Rascol O 2000 France B L -­ 268 179 89 -­ 113/66 52/57 -­ 63.0 ± 9.0 63.0 ± 9.0 -­

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, Levodopa; NR, not
reported.
LI et al.
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F I G U R E   2   Cochrane system bias
evaluations of included literatures [Colour
figure can be viewed at wileyonlinelibrary.
com]
10,22-44
controlled trials are shown in (Figure 1). The study included
6911 cases of PD patients, and most of them were treated by pla-
cebo. The included literatures in the study were published from the
year 2000 to 2014. 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 characteris-
tics of included literatures are shown in Table 1, and Cochrane bias
evaluation is shown in Figure 2.
3.2 | 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 inci-
dence for nausea was higher in patients who took ropinirole, ro-
tigotine, entacapone, and sumanirole compared to the placebo
(OR = 0.44, 95% CI = 0.25-­0.78; OR = 0.51, 95% CI = 0.29-­0.87;
OR = 0.51, 95% CI = 0.30-­0.88; OR = 0.43, 95% CI = 0.30-­0.63,
respectively) whereby the incidence of ropinirole was relatively
higher than bromocriptine (OR = 2.31, 95% CI = 1.12-­4.74). 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 = 0.15-­0.61; OR = 0.44,
95% CI = 0.22-­0.88; OR = 0.18, 95% CI = 0.06-­0.56; OR = 0.37,
95% CI = 0.17-­0.82; OR = 0.30, 95% CI = 0.01-­8.33, respectively),
whereas compared with levodopa, ropinirole presented with higher
incidence of dyskinesia on PD (OR = 3.55, 95% CI = 1.76-­7.14). 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 = 0.16-­0.90; OR = 0.23, 95%
CI = 0.07-­0.82; OR = 0.17, 95% CI = 0.04-­0.84; OR = 0.32, 95%
CI = 0.13-­0.82, respectively) whereby the efficacy of bromocrip-
tine was inferior to piribedil (OR = 0.33, 95% CI = 0.13-­0.84).
The onset of dizziness was less apparent in patients taking of
placebo compared to that of sumanirole (OR = 0.41, 95% CI = 0.26-­
0.65). The incidence of ropinirole was lower than that of pergolide
in terms of constipation (OR = 0.28, 95% CI = 0.11-­0.75). The in-
cidence somnolence was lower in patients who took ropinirole
compared to those who took sumanirole (OR = 1.75, 95% CI = 1.11-­
2.75; Table 3).
|
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3.3 | The evidence of network relationship
Among the 24 included studies, majority of the PD patients took pla-
cebo 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 reac-
tions of ropinirole, rotigotine, entacapone, and sumanirole were ob-
viously higher than that of placebo (OR = 2.48, 95% CI = 1.40-­4.28;
OR = 2.20, 95% CI = 1.27-­3.74; OR = 2.25, 95% CI = 1.19-­4.26;
OR = 2.12, 95% CI = 1.02-­4.35, respectively). As for dyskinesia, the
incidence rate of ropinirole was obviously higher than that of the pla-
cebo (OR = 3.99, 95% CI = 1.22-­15.05). Additionally, patients who
took pramipexole had higher incidence rates of hallucinations com-
pared to those who took the placebo (OR = 7.56, 95% CI = 1.01-­61.27;
Appendix A1; Figure 4). We also found that in terms of dizziness, con-
stipation, 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 rop-
inirole was high (dyskinesia: 80.5%; somnolence: 69.4%), and the in-
cidence 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
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832       LI et al.

T A B L E   2   Direct comparison results of nausea, dyskinesia and hallucination

Events/Total Pairwise meta-­analysis

Included studies Comparisons Drug1 Drug2 OR (95%CI) I2 Ph

Nausea

4 studies A vs B 77/757 180/861 0.44 (0.25-­0.78) 73.4% 0.010

1 study A vs C 10/229 8/231 1.27 (0.49-­3.29) NA NA

5 studies A vs D 56/510 167/794 0.51 (0.29-­0.87) 60.0% 0.040

5 studies A vs E 22/613 60/790 0.51 (0.30-­0.88) 46.5% 0.113

1 study A vs F 1/30 1/30 1.00 (0.06-­16.76) NA NA

3 studies A vs G 14/151 33/255 0.71 (0.37-­1.39) 0.0% 0.428

2 studies A vs H 47/517 97/519 0.43 (0.30-­0.63) 0.0% 0.913

1 study A vs K 0/10 3/10 0.10 (0.00-­2.28) NA NA

1 study B vs D 36/228 29/215 1.20 (0.71-­2.04) NA NA

2 studies B vs H 114/512 97/519 1.26 (0.49-­3.24) 89.1% 0.002

1 study B vs I 40/131 12/75 2.31 (1.12-­4.74) NA NA

2 studies B vs L 113/283 60/193 1.21 (0.80-­1.82) 42.9% 0.145

1 study C vs E 8/231 13/227 0.59 (0.24-­1.45) NA NA

1 study D vs G 35/204 26/201 1.39 (0.80-­2.42) NA NA

1 study G vs K 0/10 3/10 0.10 (0.00-­2.28) NA NA

1 study I vs J 40/215 36/210 1.10 (0.67-­1.82) NA NA

Dyskinesia

2 studies A vs B 11/436 36/431 0.30 (0.15-­0.61) 38.9% 0.201

1 study A vs C 9/229 12/231 0.75 (0.31-­1.81) NA NA

3 studies A vs D 13/296 40/398 0.44 (0.22-­0.88) 0.0% 0.426

6 studies A vs E 40/447 74/662 0.59 (0.27-­1.28) 61.1% 0.036

2 studies A vs G 3/111 32/211 0.18 (0.06-­0.56) 0.0% 0.745

1 study A vs H 9/314 23/315 0.37 (0.17-­0.82) NA NA

1 study A vs K 0/10 1/10 0.30 (0.01-­8.33) NA NA

1 study B vs H 22/310 23/315 0.97 (0.53-­1.78) NA NA

2 studies B vs I 24/168 11/114 1.65 (0.77-­3.53) 0.0% 0.478

1 study B vs L 23/89 16/179 3.55 (1.76-­7.14) NA NA

1 study C vs E 12/231 14/227 0.83 (0.38-­1.84) NA NA

1 study D vs G 24/204 31/201 0.73 (0.41-­1.30) NA NA

1 study G vs K 1/10 1/10 1.00 (0.05-­18.57) NA NA

1 study I vs J 10/215 6/210 1.66 (0.59-­4.65) NA NA

Hallucination

2 studies A vs B 8/436 22/431 0.38 (0.16-­0.90) 43.7% 0.149

1 study A vs C 3/229 5/231 0.60 (0.14-­2.54) NA NA

2 studies A vs D 3/188 18/301 0.23 (0.07-­0.82) 0.0% 0.822

5 studies A vs E 13/570 28/799 0.68 (0.21-­2.17) 55.0% 0.038

2 studies A vs G 2/111 17/211 0.17 (0.04-­0.84) 0.0% 0.685

1 study A vs H 6/314 18/315 0.32 (0.13-­0.82) NA NA

1 study A vs K 1/10 4/10 0.17 (0.01-­1.88) NA NA

1 study B vs H 10/310 18/315 0.55 (0.25-­1.21) NA NA

2 studies B vs I 11/168 3/114 2.36 (0.61-­9.15) 0.0% 0.521

1 study C vs E 5/231 8/227 0.61 (0.20-­1.88) NA NA

1 study D vs G 10/204 14/201 0.69 (0.30-­1.59) NA NA

1 study G vs K 3/10 4/10 0.64 (0.10-­4.10) NA NA

1 study I vs J 6/215 17/210 0.33 (0.13-­0.84) 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, Levodopa. Bolded numbers represent the differences are of significance.
LI et al. |
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T A B L E   3   Direct comparison results of dizziness, constipation and somnolence

Events/Total Pairwise meta-­analysis

Included studies Comparisons Drug1 Drug2 OR (95% CI) I2 Ph

Dizziness
4 studies A vs B 50/757 102/861 0.62 (0.30-­1.27) 73.4% 0.010
1 study A vs C 4/229 6/231 0.67 (0.19-­2.39) NA NA
4 studies A vs D 43/409 71/590 0.81 (0.35-­1.89) 71.4% 0.015
2 studies A vs E 28/306 26/300 1.04 (0.56-­1.93) 0.0% 0.416
1 study A vs F 1/30 1/30 1.00 (0.06-­16.76) NA NA
2 studies A vs G 7/50 9/54 0.82 (0.28-­2.40) 0.0% 0.886
2 studies A vs H 30/517 68/519 0.41 (0.26-­0.65) 21.4% 0.259
1 study A vs J 1/54 2/61 0.56 (0.05-­6.32) NA NA
1 study A vs K 1/10 1/10 1.00 (0.05-­18.57) NA NA
1 study B vs D 17/228 14/215 1.16 (0.56-­2.41) NA NA
2 studies B vs H 78/512 68/519 1.19 (0.84-­1.70) 49.1% 0.146
1 study B vs I 31/168 24/114 0.92 (0.50-­1.68) 0.0% 0.486
2 studies B vs L 39/193 51/283 1.19 (0.73-­1.92) 13.2% 0.283
1 study C vs E 6/231 6/227 0.98 (0.31-­3.09) NA NA
1 study G vs K 1/10 1/10 1.00 (0.05-­18.57) NA NA
1 study I vs J 30/215 31/210 0.94 (0.54-­1.61) NA NA
Constipation
2 studies A vs B 11/321 22/430 0.63 (0.30-­1.32) 0.0% 0.522
1 study A vs C 1/229 3/231 0.33 (0.03-­3.23) NA NA
4 studies A vs D 17/409 31/590 0.77 (0.29-­2.08) 51.9% 0.014
5 studies A vs E 30/620 50/784 0.57 (0.13-­2.51) 80.1% 0.001
1 study A vs G 3/10 2/10 1.71 (0.22-­13.41) NA NA
1 study A vs H 7/203 14/204 0.48 (0.19-­1.23) NA NA
1 study A vs K 3/10 2/10 1.71 (0.22-­13.41) NA NA
1 study B vs D 9/228 7/215 1.22 (0.45-­3.34) NA NA
1 study B vs H 13/202 14/204 0.93 (0.43-­2.04) NA NA
1 study B vs I 1/37 2/39 0.51 (0.04-­5.92) NA NA
2 studies B vs K 7/141 14/85 0.28 (0.11-­0.75) 36.7% 0.209
1 study B vs L 11/89 17/179 1.34 (0.60-­3.01) NA NA
1 study C vs E 3/231 4/227 0.73 (0.16-­3.31) NA NA
1 study I vs J 22/215 14/210 1.60 (0.79-­3.21) NA NA
Somnolence
4 studies A vs B 61/757 134/861 0.54 (0.22-­1.31) 85.8% 0.001
1 study A vs C 2/229 3/231 0.67 (0.11-­4.05) NA NA
5 studies A vs D 57/510 126/794 0.73 (0.34-­1.55) 72.8% 0.005
3 studies A vs E 15/420 15/413 0.94 (0.44-­2.04) 22.4% 0.276
1 study A vs G 8/101 24/201 0.63 (0.27-­1.47) NA NA
3 studies A vs H 59/827 96/834 0.58 (0.30-­1.13) 72.8% 0.025
1 study B vs D 28/228 23/215 1.17 (0.65-­2.10) NA NA
1 study B vs H 63/202 42/204 1.75 (1.11-­2.75) NA NA
2 studies B vs L 30/193 55/283 1.14 (0.31-­4.10) 78.9% 0.030
1 study C vs E 3/231 3/227 0.98 (0.20-­4.92) NA NA
1 study D vs G 25/204 24/201 1.03 (0.57-­1.87) 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, Levodopa, Bolded numbers represent the differences are of significance.
 |
834       LI et al.

Nausea Dyskinesia
(A) (B)
Placebo Placebo

4 studies
2 studies

Ropinirole 1 study Ropinirole

Levodopa
Levodopa
2 studies
1 study
Pergolide 1 study 1 study
1 study Pergolide
Rasagiline Rasagiline
1 study
3 studies
5 studies 1 study
1 study
Piribedil 1 study 1 study
5 studies 1 study 6 studies
2 studies Piribedil
Rotigotine
Rotigotine
1 study
1 study
1 study 2 studies
1 study 1 study
2 studies
2 studies

Bromocriptine 3 studies

Entacapone Bromocriptine
1 study 1 study
Entacapone
Apomorphine
Sumanirole Sumanirole Pramipexole
Pramipexole

(C) (D)
Hallucination Dizziness
Placebo Placebo

4 studies
2 studies
Ropinirole
1 study
2 studies
Pergolide
Ropinirole Levodopa

1 study
1 study 1 study 1 study
Pergolide
Piribedil 1 study Rasagiline
Rasagiline 2 studies
2 studies 1 study 4 studies

1 study
1 study Piribedil
1 study 1 study
5 studies
2 studies
2 studies Rotigotine
1 study
2 studies
2 studies
Rotigotine 1 study 1 study
Bromocriptine
2 studies 1 study
1 study

1 study Bromocriptine Entacapone

Sumanirole
Apomorphine
Entacapone Sumanirole
Pramipexole Pramipexole

(E) (F)
Constipation Somnolence
Placebo Placebo

2 studies
4 studies
1 study
Levodopa Ropinirole
Ropinirole
2 studies
1 study
1 study Levodopa
2 studies
Pergolide Rasagiline
1 study 3 studies
2 studies 1 study
4 studies
5 studies
1 study 1 study 1 study Rasagiline
1 study
Piribedil
1 study 1 study Sumanirole
3 studies
5 studies
Rotigotine

1 study 1 study

Pramipexole 1 study
Bromocriptine
Entacapone Rotigotine
Pramipexole

Sumanirole Entacapone

F I G U R E   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]
LI et al. |
      835

(A)

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;
Nausea

0.856
Comparison Odds Ratio (95% CI)

NR
NR
NR
NR
NR
NR
NR
So
B vs A 2.48 (1.40, 4.28)
C vs A 1.03 (0.30, 3.48)

0.278
0.635
0.311
0.319
D vs A 2.20 (1.27, 3.74)

NR
NR
NR
NR
Co E vs A 2.25 (1.19, 4.26)
F vs A 1.01 (0.03, 32.75)

0.971
0.963
0.860
0.980
0.955
G vs A 1.60 (0.66, 3.75)

NR
NR
NR
Di

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)

0.890
NR
NR
NR
NR
NR
NR
NR
Ha

K vs A 5.88 (0.61, 72.92)

L vs A 1.96 (0.69, 5.12)

0.699 0.02 1 80

NR
NR
NR
NR
NR
NR
NR
Dy

(B) Dyskinesia
P values

Comparison Odds Ratio (95% CI)

T A B L E   4   OR values and P values of direct and indirect pairwise comparisons of seven treatment modalities under six endpoint outcomes

0.856
0.864

B vs A 3.99 (1.22, 15.05)

NR
NR
NR
NR
NR
NR
Na

C vs A 1.29 (0.30, 6.07)

D vs A 2.26 (0.79, 6.40)
0.73

NR
NR
NR
NR
NR
NR
NR

E vs A 1.55 (0.79, 3.39)

So

F vs A 3.28 (0.79, 12.54)

G vs A 3.50 (0.81, 16.27)
0.31
2.20
9.00
0.11

NR
NR
NR
NR
Co

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)
1.10
1.10
0.98
2.20
1.80

NR
NR
NR
Di

K vs A 1.14 (0.15, 9.09)

0.05 1 50
1.10
NR
NR
NR
NR
NR
NR
NR
Ha

G, Pramipexole; H, Sumanirole; I, Bromocriptine; J, Piribedil; K, Pergolide; L, Levodopa; NR, not reported.

(C) Hallucination
Indirect OR values

Comparison Odds Ratio (95% CI)

0.60
NR
NR
NR
NR
NR
NR
NR

B vs A 3.39 (0.63, 19.91)

Dy

C vs A 1.15 (0.12, 11.66)

D vs A 5.20 (0.82, 34.90)
0.90
0.90

NR
NR
NR
NR
NR
NR
Na

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)
0.85

NR
NR
NR
NR
NR
NR
NR
So

H vs A 1.24 (0.08, 21.77)

I vs A 3.90 (0.12, 165.26)
J vs A 11.42 (0.60, 172.27)
5.10
0.72
0.56
1.60

NR
NR
NR
NR
Co

0.08 1 300
1.10
1.10
0.85
2.10
1.80

F I G U R E   4   The relative relationship forest diagram showing

NR
NR
NR
Di

the improvement of nausea, dyskinesia, and hallucination in

the 11 drugs. (A  =  placebo; B  =  ropinirole; C  =  rasagiline; D 
1.50

=  rotigotine; E  =  entacapone; F  =  apomorphine; G  =  pramipexole;

NR
NR
NR
NR
NR
NR
NR
Ha

H  =  sumanirole; I  =  bromocriptine; J  =  piribedil; K  =  pergolide;

Direct OR values

L  =  levodopa) (Note: all comparisons in the figure were based on

1.40

placebo as a control, 95% of the range of confidence intervals located

NR
NR
NR
NR
NR
NR
NR
Dy

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
0.74
0.80

= 1.40-2.48 (the range of it located right of 1), this means compared

NR
NR
NR
NR
NR
NR
Na

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

comparisons

(36.6%) in terms of constipation (Table 5). However, the results in-

Pairwise

G vs D
D vs B
K vs A
B vs A

K vs B
J vs A

I vs B

volved in pergolide are based on a small number of samples, so they

J vs I

need further validation.

 |
836       LI et al.

T A B L E   5   SUCRA values of twelve treatment modalities under 6 endpoint outcomes

SUCRA values

Treatments Nausea Dyskinesia Hallucination Dizziness Constipation Somnolence

A 0.210 0.202 0.167 0.252 0.366 0.234

B 0.743 0.805 0.554 0.668 0.419 0.694
C 0.277 0.359 0.262 0.439 0.552 0.434
D 0.657 0.574 0.660 0.603 0.510 0.573
E 0.661 0.425 0.324 0.320 0.577 0.306
F 0.403 NR NR 0.368 NR NR
G 0.455 0.715 0.734 0.404 0.430 0.534
H 0.616 0.724 0.630 0.667 0.528 0.629
I 0.298 0.567 0.280 0.663 0.623 NR
J 0.270 0.388 0.583 0.670 0.513 NR
K 0.835 0.456 0.798 0.436 0.591 NR
L 0.572 0.311 NR 0.528 0.378 0.600

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, Levodopa; NR, Not reported, Bold font indictaes the SUCRA is relatively higher
when compared with other interventions.

4 |  DISCUSSION si‑milar adverse reactions in PD patients treated with ropinirole.29,48

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 im-
provement in the general conditions has been clearly seen, some det-
rimental 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 con-
firmed that the incidences of adverse reaction of pergolide, ropinirole,
piribedil, and bromocriptine were the highest through direct compari-
son and a mixed treatment comparison.
The direct comparison results showed that the incidences of ad-
verse 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 af-
finities 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 re-
ceptor 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 ropini-
role was similar to those found in the present study. Both studies
showed high incidences of several adverse reactions induced by
47
ropinirole such as dyskinesia, somnolence. Previous studies have
also supported out findings that with the results of high incidence of
In the present study, we found that piribedil produced the highest
incidence of dizziness symptoms. Piribedil is a nonergotaminic do-
pamine 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 dysfunc-
tions, 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 reac-
tions 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 in-
terventions, we are unable to perform a cluster diagram and directly
show results. Additionally, we only found one literature that inves-
tigates 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
LI et al.
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 infor-
mation for further development of new drugs to treat PD based on the
natures of each drug.
ACKNOWLE DG ME NTS
We would like to acknowledge the helpful comments on this article
received from our reviewers.
CO NFLI CT OF I NTE RE S TS
The authors declare no conflict of interest.
O RCI D
Jing Bai  http://orcid.org/0000-0002-2314-7406
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Engl J Med. 2000;342:1484‐1491.
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cns.12727
APPENDIX A1
LI et al.

ODDS RATIOS AND 95 % CONFIDENCE INTERVALS OF ELEVEN DRUGS IN THE TREATM EN T O F PA RK I N S O N I N TERM S O F
NAUSEA, DYSKINESIA, AND HALLUCINATION.

Nausea
Placebo 2.48 (1.40, 1.03 (0.30, 2.20 (1.27, 2.25 (1.19, 1.01 (0.03, 1.60 (0.66, 2.12 (1.02, 1.07 (0.26, 0.94 (0.16, 5.38) 5.88 (0.61, 1.96 (0.69,
4.28) 3.48) 3.74) 4.26) 32.75) 3.75) 4.35) 3.92) 72.92) 5.12)
0.40 (0.23, Ropinirole 0.41 (0.11, 0.88 (0.44, 0.91 (0.38, 0.41 (0.01, 0.64 (0.24, 0.85 (0.41, 0.43 (0.12, 0.38 (0.07, 1.96) 2.39 (0.23, 0.78 (0.33,
0.72) 1.59) 1.80) 2.15) 13.54) 1.76) 1.80) 1.45) 30.06) 1.76)
0.97 (0.29, 2.45 (0.63, Rasagiline 2.13 (0.57, 2.19 (0.66, 1.00 (0.02, 1.55 (0.35, 2.06 (0.50, 1.04 (0.16, 0.93 (0.10, 7.97) 5.87 (0.45, 1.90 (0.38,
3.39) 9.51) 8.35) 7.85) 37.53) 7.03) 8.68) 6.41) 91.67) 9.12)
0.46 (0.27, 1.13 (0.56, 0.47 (0.12, Rotigotine 1.03 (0.45, 0.46 (0.01, 0.73 (0.30, 0.96 (0.41, 0.49 (0.11, 0.43 (0.07, 2.61) 2.70 (0.27, 0.89 (0.29,
0.79) 2.29) 1.74) 2.38) 15.18) 1.75) 2.36) 1.93) 34.06) 2.61)
0.44 (0.23, 1.10 (0.46, 0.46 (0.13, 0.97 (0.42, Entacapone 0.45 (0.01, 0.70 (0.24, 0.94 (0.35, 0.48 (0.10, 0.42 (0.06, 2.73) 2.64 (0.25, 0.87 (0.25,
0.84) 2.61) 1.52) 2.21) 15.13) 2.04) 2.41) 2.03) 34.62) 2.74)
0.99 (0.03, 2.45 (0.07, 1.00 (0.03, 2.18 (0.07, 2.21 (0.07, Apomorphine 1.59 (0.05, 2.04 (0.06, 1.03 (0.03, 0.93 (0.02, 5.88 (0.10, 1.89 (0.05,
39.19) 99.40) 46.04) 90.31) 87.63) 66.97) 86.77) 54.07) 51.53) 461.54) 85.64)
0.63 (0.27, 1.55 (0.57, 0.65 (0.14, 1.37 (0.57, 1.42 (0.49, 0.63 (0.01, Pramipexole 1.32 (0.42, 0.67 (0.13, 0.59 (0.08, 4.10) 3.71 (0.38, 1.22 (0.32,
1.52) 4.18) 2.83) 3.39) 4.23) 21.63) 4.07) 3.11) 44.49) 4.35)
0.47 (0.23, 1.18 (0.56, 0.49 (0.12, 1.04 (0.42, 1.06 (0.41, 0.49 (0.01, 0.76 (0.25, Sumanirole 0.50 (0.12, 0.45 (0.07, 2.69) 2.78 (0.27, 0.92 (0.29,
0.98) 2.43) 2.01) 2.46) 2.86) 17.31) 2.38) 2.04) 38.79) 2.71)
0.94 (0.26, 2.33 (0.69, 0.96 (0.16, 2.06 (0.52, 2.10 (0.49, 0.97 (0.02, 1.49 (0.32, 1.99 (0.49, Bromocriptine 0.90 (0.30, 2.66) 5.64 (0.41, 1.84 (0.41,
3.80) 8.29) 6.17) 8.87) 9.89) 36.89) 7.87) 8.52) 96.73) 8.42)
1.06 (0.19, 2.63 (0.51, 1.07 (0.13, 2.32 (0.38, 2.36 (0.37, 1.08 (0.02, 1.69 (0.24, 2.22 (0.37, 1.12 (0.38, Piribedil 6.35 (0.36, 2.03 (0.32,
6.26) 13.78) 9.60) 14.61) 16.18) 48.46) 12.60) 14.18) 3.33) 130.03) 13.20)
0.17 (0.01, 0.42 (0.03, 0.17 (0.01, 0.37 (0.03, 0.38 (0.03, 0.17 (0.00, 0.27 (0.02, 0.36 (0.03, 0.18 (0.01, 0.16 (0.01, 2.79) Pergolide 0.33 (0.02,
1.65) 4.31) 2.20) 3.68) 4.00) 10.28) 2.63) 3.73) 2.44) 3.92)
0.51 (0.20, 1.28 (0.57, 0.53 (0.11, 1.13 (0.38, 1.15 (0.36, 0.53 (0.01, 0.82 (0.23, 1.08 (0.37, 0.54 (0.12, 0.49 (0.08, 3.14) 3.06 (0.26, Levodopa
1.45) 3.01) 2.63) 3.40) 3.97) 19.28) 3.12) 3.43) 2.41) 45.72)
Dyskinesia
Placebo 3.99 (1.22, 1.29 (0.30, 2.26 (0.79, 1.55 (0.79, 3.28 (0.79, 3.50 (0.81, 2.28 (0.39, 1.32 (0.11, 1.57 (0.03, 1.14 (0.15,
15.05) 6.07) 6.40) 3.39) 12.54) 16.27) 13.71) 17.92) 33.53) 9.09)
0.25 (0.07, Ropinirole 0.32 (0.04, 0.56 (0.11, 0.39 (0.09, 0.82 (0.11, 0.89 (0.20, 0.56 (0.16, 0.33 (0.04, 0.38 (0.01, 9.52) 0.28 (0.06,
0.82) 2.22) 2.67) 1.58) 4.82) 3.62) 2.00) 2.94) 1.36)
0.77 (0.16, 3.11 (0.45, Rasagiline 1.73 (0.27, 1.20 (0.28, 2.54 (0.32, 2.71 (0.33, 1.77 (0.16, 1.01 (0.05, 1.17 (0.02, 0.87 (0.07,
3.34) 22.34) 10.34) 5.43) 18.20) 24.20) 17.82) 19.60) 36.58) 11.03)
0.44 (0.16, 1.80 (0.37, 0.58 (0.10, Rotigotine 0.69 (0.20, 1.47 (0.37, 1.55 (0.26, 1.02 (0.13, 0.60 (0.04, 0.68 (0.01, 0.50 (0.05,
1.26) 9.47) 3.69) 2.60) 5.46) 10.23) 8.62) 9.54) 15.81) 5.09)
|

(Continues)
      839
 |
840      

A P P E N D I X A 1   (Continued)

0.64 (0.29, 2.56 (0.63, 0.83 (0.18, 1.45 (0.38, Entacapone 2.13 (0.41, 2.25 (0.42, 1.46 (0.22, 0.85 (0.06, 0.99 (0.02, 0.73 (0.09,
1.26) 11.31) 3.59) 5.04) 9.55) 12.17) 10.07) 12.41) 22.69) 6.32)
0.30 (0.08, 1.23 (0.21, 0.39 (0.05, 0.68 (0.18, 0.47 (0.10, Pramipexole 1.07 (0.14, 0.69 (0.07, 0.40 (0.03, 0.47 (0.01, 9.65) 0.34 (0.03,
1.26) 8.95) 3.13) 2.74) 2.46) 8.98) 7.36) 7.46) 4.35)
0.29 (0.06, 1.13 (0.28, 0.37 (0.04, 0.64 (0.10, 0.44 (0.08, 0.94 (0.11, Sumanirole 0.64 (0.10, 0.38 (0.03, 0.43 (0.01, 0.32 (0.04,
1.23) 5.01) 3.06) 3.86) 2.39) 7.14) 4.70) 5.02) 13.18) 2.87)
0.44 (0.07, 1.78 (0.50, 0.57 (0.06, 0.98 (0.12, 0.69 (0.10, 1.46 (0.14, 1.57 (0.21, Bromocriptine 0.59 (0.10, 0.68 (0.01, 0.49 (0.07,
2.54) 6.27) 6.11) 7.52) 4.61) 13.59) 10.47) 3.41) 23.10) 3.83)
0.75 (0.06, 3.00 (0.34, 0.99 (0.05, 1.67 (0.10, 1.18 (0.08, 2.48 (0.13, 2.66 (0.20, 1.69 (0.29, Piribedil 1.14 (0.01, 0.85 (0.06,
8.78) 26.78) 18.44) 24.25) 16.10) 39.20) 36.51) 9.95) 61.30) 12.83)
0.64 (0.03, 2.65 (0.11, 0.85 (0.03, 1.47 (0.06, 1.01 (0.04, 2.13 (0.10, 2.32 (0.08, 1.47 (0.04, 0.87 (0.02, Pergolide 0.75 (0.02,
34.36) 150.86) 57.89) 81.78) 57.82) 102.16) 152.39) 95.56) 81.25) 54.44)
0.88 (0.11, 3.55 (0.74, 1.15 (0.09, 1.99 (0.20, 1.37 (0.16, 2.92 (0.23, 3.13 (0.35, 2.02 (0.26, 1.18 (0.08, 1.33 (0.02, Levodopa
6.50) 17.02) 13.73) 19.52) 11.40) 31.30) 26.46) 14.73) 17.33) 49.50)
Hallucination
Placebo 3.39 (0.63, 1.15 (0.12, 5.20 (0.82, 1.68 (0.48, 7.56 (1.01, 4.41 (0.51, 1.24 (0.08, 3.90 (0.12, 11.42 (0.60,
19.91) 11.66) 34.90) 5.38) 61.27) 42.17) 21.77) 165.26) 172.27)
0.29 (0.05, Ropinirole 0.34 (0.02, 1.64 (0.12, 0.47 (0.05, 2.33 (0.15, 1.32 (0.15, 0.39 (0.05, 1.17 (0.06, 3.55 (0.10,
1.59) 5.73) 19.35) 3.77) 32.41) 11.49) 3.51) 28.53) 80.42)
0.87 (0.09, 2.92 (0.17, Rasagiline 4.47 (0.23, 1.43 (0.14, 6.50 (0.31, 4.12 (0.16, 1.00 (0.03, 3.76 (0.05, 9.68 (0.24,
8.10) 51.71) 77.76) 11.81) 126.20) 88.64) 39.57) 273.13) 322.38)
0.19 (0.03, 0.61 (0.05, 0.22 (0.01, Rotigotine 0.31 (0.03, 1.37 (0.19, 0.85 (0.05, 0.25 (0.01, 0.75 (0.01, 2.30 (0.10,
1.23) 8.42) 4.31) 2.82) 11.15) 17.01) 7.09) 47.42) 41.35)
0.59 (0.19, 2.11 (0.27, 0.70 (0.08, 3.23 (0.35, Entacapone 4.73 (0.44, 2.62 (0.23, 0.75 (0.04, 2.31 (0.06, 7.10 (0.30,
2.10) 18.76) 6.97) 31.18) 51.40) 36.93) 17.68) 135.17) 145.47)
0.13 (0.02, 0.43 (0.03, 0.15 (0.01, 0.73 (0.09, 0.21 (0.02, Pramipexole 0.60 (0.03, 0.17 (0.01, 0.53 (0.01, 1.56 (0.10,
0.99) 6.73) 3.27) 5.40) 2.29) 12.58) 5.69) 36.39) 18.79)
0.23 (0.02, 0.76 (0.09, 0.24 (0.01, 1.18 (0.06, 0.38 (0.03, 1.67 (0.08, Sumanirole 0.27 (0.01, 0.89 (0.02, 2.53 (0.06,
1.98) 6.73) 6.39) 19.45) 4.44) 33.69) 6.41) 43.77) 72.40)
0.81 (0.05, 2.56 (0.28, 1.00 (0.03, 4.02 (0.14, 1.33 (0.06, 5.81 (0.18, 3.72 (0.16, Bromocriptine 3.30 (0.32, 8.54 (0.13,
12.21) 22.10) 28.81) 105.70) 25.78) 167.62) 79.99) 32.95) 395.94)
0.26 (0.01, 0.85 (0.04, 0.27 (0.00, 1.33 (0.02, 0.43 (0.01, 1.88 (0.03, 1.13 (0.02, 0.30 (0.03, Piribedil 2.89 (0.02,
8.33) 17.32) 18.32) 67.46) 17.12) 107.18) 50.55) 3.09) 207.09)
0.09 (0.01, 0.28 (0.01, 0.10 (0.00, 0.43 (0.02, 0.14 (0.01, 0.64 (0.05, 0.40 (0.01, 0.12 (0.00, 0.35 (0.00, Pergolide
1.66) 9.69) 4.11) 10.32) 3.33) 9.72) 16.52) 7.95) 44.79)
Bolded numbers represent the differences are of significance.
LI et al.
 LI et al.

APPENDIX A2

ODDS RATIOS AND 9 5% CONFIDENC E IN TERVALS OF ELEVEN DRUGS IN THE TREATM EN T O F PA RK I N S O N I N TERM S O F
DIZZINESS, CONSTIPATION, AND SOMNOLENCE.

Dizziness
Placebo 1.89 (0.98, 1.25 (0.28, 1.69 (0.89, 1.06 (0.40, 0.73 (0.03, 1.15 (0.31, 1.92 (0.84, 4.09) 1.96 (0.64, 2.06 (0.51, 7.88) 1.09 (0.02, 1.60 (0.49,
3.25) 5.18) 3.27) 2.73) 32.12) 4.64) 5.38) 36.55) 4.17)
0.53 (0.31, Ropinirole 0.65 (0.13, 0.89 (0.43, 0.57 (0.19, 0.40 (0.01, 0.62 (0.15, 1.01 (0.48, 2.22) 1.01 (0.41, 1.11 (0.31, 4.04) 0.60 (0.01, 0.83 (0.34,
1.02) 3.18) 2.17) 1.88) 19.17) 2.92) 2.58) 14.69) 1.96)
0.80 (0.19, 1.54 (0.31, Rasagiline 1.36 (0.30, 0.85 (0.20, 0.58 (0.02, 0.91 (0.13, 1.57 (0.29, 8.31) 1.59 (0.26, 1.66 (0.22, 0.85 (0.01, 1.28 (0.20,
3.61) 7.41) 7.20) 3.52) 33.42) 7.16) 9.96) 12.31) 32.88) 7.32)
0.59 (0.31, 1.12 (0.46, 0.73 (0.14, Rotigotine 0.62 (0.19, 0.43 (0.02, 0.67 (0.15, 1.14 (0.40, 2.97) 1.16 (0.33, 1.22 (0.26, 5.06) 0.64 (0.01, 0.94 (0.26,
1.12) 2.35) 3.33) 1.92) 20.53) 3.22) 3.55) 21.65) 2.83)
0.95 (0.37, 1.77 (0.53, 1.18 (0.28, 1.61 (0.52, Entacapone 0.70 (0.02, 1.13 (0.22, 1.79 (0.50, 6.24) 1.80 (0.44, 1.90 (0.35, 1.04 (0.02, 1.45 (0.32,
2.53) 5.38) 5.07) 5.25) 33.20) 6.08) 7.58) 10.58) 26.53) 5.84)
1.37 (0.03, 2.50 (0.05, 1.73 (0.03, 2.30 (0.05, 1.42 (0.03, Apomorphine 1.63 (0.03, 2.52 (0.05, 2.54 (0.05, 2.69 (0.05, 1.29 (0.00, 2.10 (0.04,
36.56) 69.79) 60.51) 63.64) 42.53) 54.82) 71.20) 79.47) 89.79) 507.08) 61.66)
0.87 (0.22, 1.60 (0.34, 1.10 (0.14, 1.50 (0.31, 0.89 (0.16, 0.61 (0.02, Pramipexole 1.62 (0.32, 7.46) 1.66 (0.28, 1.73 (0.24, 0.91 (0.02, 1.35 (0.22,
3.22) 6.76) 7.50) 6.60) 4.59) 34.77) 8.89) 11.35) 40.55) 6.84)
0.52 (0.24, 0.99 (0.45, 0.64 (0.12, 0.88 (0.34, 0.56 (0.16, 0.40 (0.01, 0.62 (0.13, Sumanirole 1.01 (0.30, 1.08 (0.24, 4.79) 0.59 (0.01, 0.82 (0.25,
1.19) 2.07) 3.39) 2.48) 1.98) 19.64) 3.10) 3.27) 14.87) 2.43)
0.51 (0.19, 0.99 (0.39, 0.63 (0.10, 0.86 (0.28, 0.55 (0.13, 0.39 (0.01, 0.60 (0.11, 0.99 (0.31, 3.29) Bromocriptine 1.08 (0.36, 3.12) 0.57 (0.01, 0.81 (0.22,
1.57) 2.42) 3.83) 3.07) 2.29) 20.91) 3.61) 15.97) 2.71)
0.49 (0.13, 0.90 (0.25, 0.60 (0.08, 0.82 (0.20, 0.53 (0.09, 0.37 (0.01, 0.58 (0.09, 0.93 (0.21, 4.13) 0.93 (0.32, Piribedil 0.55 (0.01, 0.75 (0.15,
1.98) 3.26) 4.57) 3.86) 2.89) 21.57) 4.16) 2.76) 13.60) 3.49)
0.92 (0.03, 1.67 (0.07, 1.17 (0.03, 1.56 (0.05, 0.96 (0.04, 0.78 (0.00, 1.10 (0.02, 1.70 (0.07, 1.74 (0.06, 1.83 (0.07, Pergolide 1.44 (0.05,
46.01) 91.40) 69.99) 81.23) 46.90) 204.17) 48.25) 92.35) 91.68) 108.04) 80.59)
0.62 (0.24, 1.20 (0.51, 0.78 (0.14, 1.06 (0.35, 0.69 (0.17, 0.48 (0.02, 0.74 (0.15, 1.22 (0.41, 4.06) 1.23 (0.37, 1.33 (0.29, 6.57) 0.69 (0.01, Levodopa
2.05) 2.93) 4.99) 3.90) 3.09) 26.25) 4.56) 4.62) 18.71)
Constipation
Placebo 1.13 (0.15, 1.86 (0.08, 1.48 (0.30, 1.85 (0.42, 1.06 (0.03, 1.64 (0.09, 2.81 (0.03, 1.73 (0.01, 2.14 (0.13, 0.85 (0.02,
8.25) 47.12) 7.70) 8.40) 35.05) 30.31) 381.42) 493.87) 28.69) 38.33)
0.88 (0.12, Ropinirole 1.67 (0.04, 1.30 (0.14, 1.59 (0.15, 0.91 (0.02, 1.43 (0.08, 2.40 (0.04, 1.51 (0.01, 1.89 (0.13, 0.74 (0.03,
6.63) 73.45) 13.45) 21.48) 38.51) 27.67) 205.17) 326.88) 23.28) 18.77)
0.54 (0.02, 0.60 (0.01, Rasagiline 0.78 (0.02, 0.99 (0.04, 0.55 (0.00, 0.86 (0.01, 1.52 (0.01, 0.93 (0.00, 1.16 (0.02, 0.46 (0.00,
12.47) 24.60) 28.66) 24.16) 64.35) 68.59) 476.49) 507.80) 66.82) 59.23)
|

(Continues)
      841
 |
842      

A P P E N D I X A 2   (Continued)

0.68 (0.13, 0.77 (0.07, 1.28 (0.03, Rotigotine 1.25 (0.14, 0.71 (0.01, 1.11 (0.04, 1.89 (0.02, 1.17 (0.00, 1.44 (0.07, 0.57 (0.01,
3.37) 7.24) 50.40) 11.14) 33.64) 30.24) 274.45) 363.10) 27.00) 29.31)
0.54 (0.12, 0.63 (0.05, 1.01 (0.04, 0.80 (0.09, Entacapone 0.56 (0.01, 0.90 (0.03, 1.53 (0.01, 0.91 (0.00, 1.17 (0.05, 0.47 (0.01,
2.38) 6.79) 24.03) 7.13) 24.87) 23.06) 239.78) 321.23) 21.77) 25.36)
0.94 (0.03, 1.09 (0.03, 1.83 (0.02, 1.41 (0.03, 1.77 (0.04, Pramipexole 1.55 (0.02, 2.60 (0.01, 1.58 (0.00, 2.05 (0.06, 0.79 (0.01,
38.10) 50.40) 243.87) 76.63) 97.52) 156.07) 1008.62) 1308.52) 79.43) 134.42)
0.61 (0.03, 0.70 (0.04, 1.16 (0.01, 0.90 (0.03, 1.11 (0.04, 0.65 (0.01, Sumanirole 1.68 (0.01, 1.07 (0.00, 1.32 (0.03, 0.51 (0.01,
11.42) 12.97) 92.00) 23.47) 31.57) 54.16) 337.89) 482.09) 45.55) 44.82)
0.36 (0.00, 0.42 (0.00, 0.66 (0.00, 0.53 (0.00, 0.66 (0.00, 0.38 (0.00, 0.60 (0.00, Bromocriptine 0.60 (0.03, 0.77 (0.00, 0.31 (0.00,
32.50) 22.52) 191.11) 58.67) 83.78) 86.27) 94.71) 14.71) 93.11) 50.38)
0.58 (0.00, 0.66 (0.00, 1.08 (0.00, 0.85 (0.00, 1.10 (0.00, 0.63 (0.00, 0.93 (0.00, 1.67 (0.07, Piribedil 1.27 (0.00, 0.51 (0.00,
148.45) 106.68) 735.90) 244.57) 374.65) 354.38) 354.48) 36.05) 377.58) 194.69)
0.47 (0.03, 0.53 (0.04, 0.86 (0.01, 0.69 (0.04, 0.86 (0.05, 0.49 (0.01, 0.76 (0.02, 1.30 (0.01, 0.79 (0.00, Pergolide 0.40 (0.01,
7.62) 7.73) 62.09) 14.25) 22.10) 18.17) 32.66) 236.91) 346.22) 26.30)
1.17 (0.03, 1.35 (0.05, 2.17 (0.02, 1.76 (0.03, 2.15 (0.04, 1.27 (0.01, 1.96 (0.02, 3.26 (0.02, 1.96 (0.01, 2.50 (0.04, Levodopa
50.36) 30.92) 294.69) 86.80) 126.36) 146.96) 147.52) 754.97) 948.55) 142.55)
Somnolence
Placebo 2.03 (0.85, 1.20 (0.12, 1.68 (0.73, 1.01 (0.27, 1.62 (0.33, 1.88 (0.57, 1.85 (0.34, 9.21)
4.99) 11.19) 4.08) 3.56) 8.82) 6.49)
0.49 (0.20, Ropinirole 0.59 (0.05, 0.82 (0.27, 0.49 (0.10, 0.79 (0.13, 0.92 (0.28, 0.90 (0.21, 3.29)
1.18) 6.71) 2.65) 2.34) 5.41) 3.11)
0.83 (0.09, 1.70 (0.15, Rasagiline 1.41 (0.13, 0.84 (0.09, 1.35 (0.09, 1.58 (0.12, 1.52 (0.09,
8.10) 19.24) 16.55) 8.00) 22.72) 20.87) 23.26)
0.60 (0.25, 1.22 (0.38, 0.71 (0.06, Rotigotine 0.59 (0.12, 0.97 (0.18, 1.13 (0.25, 1.11 (0.16, 5.96)
1.37) 3.69) 7.69) 2.68) 4.97) 4.70)
0.99 (0.28, 2.03 (0.43, 1.19 (0.13, 1.68 (0.37, Entacapone 1.61 (0.20, 1.87 (0.32, 1.82 (0.22,
3.64) 9.64) 11.26) 8.10) 13.35) 11.67) 13.90)
0.62 (0.11, 1.26 (0.18, 0.74 (0.04, 1.03 (0.20, 0.62 (0.07, Pramipexole 1.16 (0.15, 1.17 (0.10, 9.85)
3.07) 7.52) 11.14) 5.53) 5.00) 8.29)
0.53 (0.15, 1.09 (0.32, 0.63 (0.05, 0.89 (0.21, 0.53 (0.09, 0.86 (0.12, Sumanirole 0.99 (0.14, 5.48)
1.76) 3.55) 8.14) 3.94) 3.12) 6.84)
0.54 (0.11, 1.11 (0.30, 0.66 (0.04, 0.90 (0.17, 0.55 (0.07, 0.86 (0.10, 1.01 (0.18, Levodopa
2.93) 4.70) 10.99) 6.14) 4.59) 9.76) 7.01)
LI et al.