医薬品相互作用研究

Vol.43, No. 3（2019）43（189）医薬品相互作用研究
一
般論
文
43（3）43-52 （2019）

Comparison of drug eﬃcacy and safety for restless legs syndrome:
A Meta-analysis
Yukinaga KISHIKAWA1）, Miki SUGIYAMA2）, Yousuke NISHIKAWA3）, Junji SAKURAI4）,
Yasuhito NOBUSHI1）, Yasuhiro TSUJI5）, Taku OBARA6）, Fumiaki ISHIZAWA4）
Laboratory of Clinical Pharmacy, School of Pharmacy, Nihon University
Pharmaceutical department, Nagano Prefectural Shinsyu Medical Center
3）
Clinical Pharmacy Practice Center, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University
4）
Department of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University Wakabayashi Hospital
5）
Center for Pharmacist Education, School of Pharmacy, Nihon University
6）
Tohoku University Tohoku Medical Megabank Organization
1）

2）（Received May 15, 2019; Revised July 1, 2019; Accepted July 24, 2019）
Restless legs syndrome (RLS) is a sensory disorder characterized by sensory abnormalities (paresthesia) during
the waking state, at rest, and at sleep onset. Currently, three RLS drugs̶pramipexole, gabapentin enacarbil, androtigotine̶are approved for use in the national medical insurance system in Japan. In the present study, we
conducted a meta-analysis to compare the eﬃcacy and safety of these three drugs. The target patients were
idiopathic RLS patients who had been diagnosed as having moderate-to-severe RLS on the International Restless
Legs Syndrome Study Group Rating Scale (IRLS). The eﬃcacy end point was the mean diﬀerence of change in IRLS
score. The safety endpoint was the number of adverse eﬀects. T he eﬃcacy endpoints were integrated using theweighted mean diﬀerence (WMD) for each treatment group compare d with a placebo group. We integrated safetyassessment items using the risk diﬀerence(RD). When comparing the integrated WMDs of the three RLS
therapeutics indirectly, the reduction in IRLS scores was the highest for rotigotine, followed by pramipexole, andthen gabapentin enacarbil, but no signiﬁcant diﬀerences were found between the three drugs. With regard to safety,
a signiﬁcant diﬀerence in the integrated WMDs was found betwe en pramipexole and rotigotine; however, nosigniﬁcant diﬀerences were observed between pramipexole compa red with gabapentin enacarbil or rotigotine
compared with gabapentin enacarbil. These ﬁndings provide evid ence to support drug selection in the clinicalsetting.
Key Words: restless legs syndrome, meta-analysis , eﬃcacy, safety

Introduction

The prevalence of RLS is reported to be 1‒4% in

R estless legs syndrome (RLS) is a perceptual

Japan 1,2) . RLS is divided into primary (idiopathic),

disorder characterized by aberrant sensations during

whose cause is not found, and secondary, which

the waking state, at rest, and at sleep onset. RLS is

coexists with other diseases. Secondary RLS is often

characterized by an unpleasant sensation in the lower

accompanied by cerebrovascular disease, Parkinsonʼsextremities that the legs should be moved that starts

disease, polyneuritis, chronic renal failure (especiallyat rest, improves with exercise, and exacerbates fromin dialysis patients), and iron deﬁciency anemia,

the daytime to the evening/nighttime.

often in conditions prone to iron deﬁciency, such as

Laboratory of Clinical Pharmacy, School of Pharmacy, Nihon University 7-7-1 Narashinidai, Funabashi-shi, Chiba, 274-8555
Pharmaceutical department, Nagano Prefectural Shinsyu Medical Center 1332 Suzaka, Suzaka-shi, Nagano, 382-0091
3）
Clinical Pharmacy Practice Center, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University 4-4-1
Komatsushima, Aoba-ku, Sendai, 981-8558
4）
Department of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University Wakabayashi Hospital 2-29-1 Yamatomachi,
Wakabayashi-ku, Sendai, 984-8560
5）Center for Pharmacist Education, School of Pharmacy, Nihon University 7-7-1 Narashinidai, Funabashi-shi, Chiba, 274-8555
6）
Tohoku University Tohoku Medical Megabank Organization 2-1 Seiryou-cho, Aoba-ku, Sendai, 980-8573
e-mail: kishikawa.yukinaga@nihon-u.ac.jp
TEL: 047-465-1107 FAX: 047-465-11071）2）

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during pregnancy. If RLS develops, aﬀected

the MEDLINE database and The Cochrane Library

individuals feel discomfort in the lower extremities

with the following conditions: “restless legs

and feel that they must move their legs. Symptoms

syndrome pramipexole placebo” OR “restless legs

intensify in the evening and nighttime, and sleeps y n d r o m e g a b a p e n t i n e n a c a r b i l p l a c e b o” O R

disorders such as sleeplessness and awakening often“restless legs syndrome rotigotine placebo” andoccur, which reduces daytime activity and causes

limited the results to randomized controlled trials.

anxiety and depression, greatly aﬀecting daily life 3).
In RLS, abnormal (nociceptive) perceptions

2. Recruitment criteria

generated in resting skeletal muscle pass throughThe inclusion criteria for the literature were amyelinated nerve ﬁbers and are transmitted to therandomized controlled trial with study design, andcortical sensory area via dorsal root cells, creating an

the target patients were idiopathic RLS patientsunusual sensation. On the other hand, intrinsic

diagnosed as moderate to severe RLS on the IRLS

perceptions carrying information such as theseverity scale. The eﬃcacy endpoint was the meancontraction/relaxation of skeletal muscle travel

diﬀerence between changes in IRLS scores, and thethrough unmyelinated nerve ﬁbers to the brain, andsafety endpoint was the number of adverse events.

at the same time, suppress the sensitivity of dorsal
root cells. In other words, it is speculated that when

3. Data extraction

the stimulation of the intrinsic sensory system is

The data extracted from the document searchincreased by exercise, nociceptive perception is

included the study design (randomized, with or

suppressed and abnormal sensations are less likely

without masking), inclusion/exclusion criteria forto be transmitted to the sensory area of the cerebral

the study patients, age, sex, number of cases,

cortex.

administration period, intervention, and results of

The severity of RLS can be assessed using theInternational Restless Legs Syndrome Study Group

each evaluation item (mean diﬀerence of change in
IRLS score, number of adverse eﬀects).

Rating Scale (IRLS), which can also determine thecourse of treatment. RLS severity is classiﬁed based

4. Evaluation of research quality

on the IRLS total score as follows: 1‒10 points

The quality of the research in the targetedindicates mild RLS, 11‒20 points indicates moderate

papers was evaluated using the Jadad score 4)

RLS, 21‒30 points indicates severe RLS, 31‒40

shown below.

points indicates very severe RLS.

Jadad score:

Treatment for RLS includes both drug and1）Was the study described as randomized (thisnon-drug therapy; non-drug therapy includes

includes terms such as randomly, random, anddiscontinuation of drugs and items causing RLS,

randomization)? (Yes: 1, No: 0)

sleep hygiene instruction, appropriate exercise, etc.,

2）Was the method used to generate the sequencewhen drugs are not eﬀective. Drugs that have beenof randomization fully described andshown to be eﬀective include dopamine agonists,

appropriate (table of random numbers,

levodopa preparations, benzodiazepines, andcomputer-generated, etc.)? (Yes: 1, No: ‒1)

anticonvulsants. Currently, only three drugs are3）Was the study described as double-blind? (Yes:approved for RLS in Japan: pramipexole, gabapentin

1, No: 0)

enacarbil, and rotigotine. In the present study, the4 ）W a s t h e d o u b l e - b l i n d i n g m e t h o d f u l l yeﬃcacy and safety of these three agents were

described and appropriate (identical placebo,

compared and examined with the aim of compiling

active placebo, dummy, etc.)? (Yes: 1, No: ‒1)evidence to aid in drug selection in the clinical5）Was there a description of withdrawals andsetting.

dropouts? (Yes: 1, No: 0)
The highest possible score is 5 points, with 3 or

Methods

more points indicating a high-quality study, and 2

1. Research paper collection

or fewer points indicating a low-quality study.

We conducted a search for research papers in医薬品相互作用研究

Vol.43, No. 3（2019）45（191）

test heterogeneity. The integrated WMD and RD

5. Quality assessment
Two authors independently performed primary

and their 95% conﬁdence intervals were calculated

screening. We selected papers that each met theusing a random-eﬀects model, and eﬀectivenessselection criteria and compared the results of theand safety were evaluated statistically. The eﬃcacy

two people. Also in the secondary screening, twoand safety of each RLS treatment were comparedauthors independently read the full text andand examined using the indirect method 5).

compared the two results. When two people's
opinion was diﬀerent, the opinion of the third
party was taken in and the adoption paper was

7. Examination of publication bias
The publicat ion bias was examined using the
Kendall rank correlat ion coeﬃcient calculated

decided.

using the method of Begg6). The level ofsigniﬁcance was set at 0.10.

6. Data synthesis
The meta-analysis in the present study was
performed using StatsDirect (ver. 3,

Results

http:www.statsdirect.com/, StatsDrect Limited).

1. Search results

The eﬃcacy evaluation was integrated using the

Of the 56 research papers identiﬁed, 19 met theweighted mean diﬀerence (WMD) for each

inclusion criteria, among which, seven were on

treatment group compared with a placebo group,

pramipexole, six on gabapentin enacarbil, and six

and the safety evaluation were integrated using theon rotigotine. The research paper selection process

risk diﬀerence (RD). The I statistic (I 2 ) was used tois shown in Figure 1.

Fig.1 Study retrieval and selection

2. Content of the research papers to be analyzed

No sensitivity analysis excluding low-quality

Tables 1‒3 show the details of the papers on

studies was performed as low-quality studies werepramipexole, gabapentin enacarbil, and rotigotine,

not included in the selected papers.

respect ively, that were analyzed in the present

The inclusion criterion for the pat ients in all

study. All papers reported randomized controlled

studies was a diagn osis of m o d erate-to-severe

trials with a parallel group design and wereprimary (idiopathic) RLS on the IRLS. All studies

considered high quality (Jadad score of 3 or more).

involving patients with secondary RLS, pregnant or46（192）

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lactating women, patients with renal dysfunction,

Vol.43, No. 3（2019）

excluded.

and patients using other RLS medications wereTable 1 Study Characteristics for Trials Comparing Pramipexole and Placebo.

Table 2 Study Characteristics for Trials Comparing Gabapentin enacarbil and Placebo.

Table 3 Study Characteristics for Trials Comparing Rotigotine and Placebo.

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Vol.43, No. 3（2019）47（193）r o t i g o t i n e , r e s p e c t i v e l y. M o d e r a t e - t o - s t r o n g

3. Eﬃcacy
In total, seven, four, and six studies analyzed theeﬃcacy of pramipexole, gabapentin enacarbil, andheterogeneity was observed between each RLS
treatment compared with the placebo (Table 4).

Table 4 Pooled Eﬃcacy Endpoints (WDM) of Treatment versus Pla cebo

Signiﬁcant decreases in IRLS scores compared-5.10 to -2.18) for gabapentin enacarbil vs.

with placebo were seen in seven studies onplacebo, -5.48(95％ CI,-7.66 to -3.30) for rotigotine

pramipexole, four on gabapentin enacarbil, and six

vs. placebo. The integrated WMD showed aon rotigotine. WMD were -4.71（95 ％ CI, -5.70 tosigniﬁcant decrease compared with the placebo for-3.72）for pramipexole vs. praceco, -3.64(95 ％ CI,

all three drugs (Figs. 2‒4).

Fig.2 Meta-analysis of the IRLS for Pramipexole versus Placebo

Fig.3 Meta-analysis of the IRLS for Gabapentin enacarbil versus Placebo

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Fig.4 Meta-analysis of the IRLS for Rotigotine versus Placebo

When comparing the integrated WMDs of therotigotine, 0.77 (95 ％ CI,3.16 to -1.62) for

three RLS therapeutics indirectly, the reduction inrotigotine vs. pramipexole. No signiﬁcant

IRLS scores was the highest for rotigotine,

diﬀerences were seen between the three drugs

followed by pramipexole and then gabapentin(Table 5).

enacarbil. WMD were -1.07（95％ CI, 0.69 to -2.83）
for pramipexole vs. g abapent in enacarbil, 1.84

No publication bias was observed in all
integrations.

(95％ CI,4.46 to ‒0.78) for gabapentin enacarbil vs.
Table 5 Indirect Comparisons of Eﬃcacy of Pramipexole vs Gaba pentin enacarbil vs Rotigotiner o t i g o t i n e , r e s p e c t i v e l y. M o d e r a t e - t o - s t r o n g

4. Safety
In total, seven, six, and six studies analyzed thesafety of pramipexole, gabapentin enacarbil, andheterogeneity was observed between each RLS
treatment and the placebo (Table 6).

Table 6 Pooled Safety Endpoints (RD) of Treatment versus Placebo

In many studies, no adverse eﬀects (RD) werepramipexole vs. praceco, 0.13 (95 ％ CI, 0.05 toreported; however, three were reported in primary0.21) for gabapentin enacarbil vs. placebo, 0.20

studies with pramipexole, three with gabapentin(95 ％ CI,0.08 to 0.32) for rotigotine vs. placebo.

enacarbil, and four with rotigotine, all having

The integrated RD was signiﬁcantly diﬀerent fromsigniﬁcant diﬀerences compared with the placebo.

placebo for all three drugs (Figs. 5‒7).

R D w e r e 0 . 1 1 （ 9 5 ％ C I , 0 . 0 7 t o 0 . 1 5 ）f o r

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Fig.5 Meta-analysis of the Adverse events for Pramipexole versus Placebo

Fig.6 Meta-analysis of the Adverse events for Gabapentin enacarbil versus Placebo

Fig.7 Meta-analysis of the Adverse events for Rotigotine versus Placebo49（195）

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W i t h r e g a r d t o s a f e t y, w h e n c o m p a r i n g t h e
integrated RDs of the three RLS drugs indirectly, aVol.43, No. 3（2019）with gabapentin enacarbil (RD was -0.08 (95%CI,-0.17 to 0.03) ) (Table 7).

signiﬁcant diﬀerence was found for pramipexole

A publication bias was observed in the twocompared with rotigotine (RD was -0.1 (95%CI,

integ rat ion results in the safety review. In-0.16 to -0.02) ); however, no signiﬁcantp r a m i p e x o l e , B e g g - M a z u m d e r : Ke n d a l l ' s t a u =diﬀerences were observed between pramipexole

0.714 P = 0.03, and in gabapentin enacarbil,

compared with gabapentin enacarbil (RD was -0.02

Begg-Mazumder: Kendall's tau = 0. 733 P = 0.06.

(95%CI, -0.11 to 0.07) ) or rotigotine compared
Table 7 Indirect Comparisons of Safety of Pramipexole vs Gabapentin enacarbil vs Rotigotine

Discussion

compared with the placebo. When comparing the

In the present study, a meta-analysis was

integrated RDs of the three RLS drugs indirectly, a

conducted to compare indirectly the eﬃcacy andsigniﬁcant diﬀerence was found for pramipexole

safety of pramipexole, gabapentin enacarbil, andcompared with rotigotine. In patients withrotigotine for primary (idiopathic) RLS patientsmoderate-to-severe primary (idiopathic) RLS

diagnosed with moderate-to-severe RLS according

according to the IRLS, the safest drug, whento the IRLS. Placebo-paired comparisons werecompared at clinical doses, is considered to be

integrated using a random-eﬀects model.

pramipexole, followed by gabapentin enacarbil andIn the analysis of eﬃcacy, IRLS scores showed athen rot igot ine. Adverse eﬀects common to all

signiﬁcant decrease in all three drugs. When thepatients in the analyzed studies were headache,integrated WMDs of the three RLS drugs were

nausea, and dizziness. Further, among the threecompared indirectly in terms of eﬀectiveness, theagen ts, on l y rot igo t in e comes in the form of areduction rate in IRLS scores tended to be highest

patch, and thus, an application site reaction is afor rotigotine, followed by pramipexole and thencharacteristic adverse eﬀect. However, no patientsgabapentin enacarbil. In addition, no signiﬁcant

dropped out because of serious skin problems, anddiﬀerence was found between gabapentin

thus, it was con sidered appropriate to u se theenacarbil and rotigotine. In patients withadverse eﬀect rate as a safety evaluation item. It is

moderate-to-severe primary (idiopathic) RLS

important to take the type of adverse eﬀects

according to the IRLS, clinical doses of rotigotine

associated with each drug into account whenappeared to be most eﬀective. In this study, theconsidering the choice of treatment.

reduction rate of IRLS scores was used as an

Iftilhar.I.H et al. performed a meta-analysis ofevaluation index of eﬃcacy; however, in addition

their eﬀects on pramipexole, ropinirole, rotigotine,to the IRLS, the Clinical Global Impression scalepregabalin, gabapentin enacarbil for RLS 2 6 ) . The

and subjective sleep items (e.g., evaluation of sleep

result was that all treatments were superior todisorder) are used as an evaluation index for theplacebo. However, no signiﬁcant diﬀerence was

eﬃcacy of RLS drugs, and the Pittsburgh Sleep

found in the comparison among the drugs. These

Quality Index and the Epworth Sleepiness Scale areresults are consistent with our results. Theirused to assess daytime sleepiness. It will bemeta-analysis compares the major side eﬀects

necessary to analyze studies involving thesecommon to each drug in terms of safety, but our

indexes in future research.

study compares the number of side eﬀects. ThisIn the safety analysis, all three drugs showed asigniﬁcant risk of causing adverse eﬀects

result is considered to be important information in
drug selection.

医薬品相互作用研究

Publication bias was observed in the integrationof pramipexole and gabapentin enacarbil. Since all

Vol.43, No. 3（2019）51（197）683-691, 1997.
６）Begg CB, Mazumder M, Operating

the calculation results are low power, submission

characteristics of a rank correlation test forof research papers in this theme is desired in the

publiﬁcation bias. Biometrics., 1088-1101,

future. And this integration result should be judged

1994.

carefully on the assumption that there ispublication bias.
S ub g ro u p a na lysis was performed for highl yheterogeneous integration results, but nosigniﬁcant change was found in I 2. From this, it canbe considered that the cause is racial diﬀerences
and complications of the target patients.
This study is limited in terms of its indirectc o m p a r i s o n o f e ﬃ c a c y a n d s a f e t y. I n o r d e r t oobtain reliable evidence in the future, it is７）Ferini-Strambi L, Aarskog D, Partinen M etal.: Eﬀect of pramipexole on RLS symptom
and sleep : A rondomized, double-blind,placebo-controlled trial. Sleep Medicine., 9,874-881, 2008.
８）Högl B, Garcia-Borreguero D, Trenkwalder C
et al.: Eﬃcacy and augmentation during 6
months of double-blind pramipexole forrestless legs syndrome. Sleep Medicine., 12,351-360, 2011.

desirable to compare directly the diﬀerences in９）Zhang J, Liu B, Zheng Y et al.: Pramipexoleeﬃcacy and safety between the drugs used in thisfor Chinese people withy primary restlessstudy.

legs syndrome : a 12-week multicenter,In addition, analyzing other evaluation indexes
would enable the eﬃcacy and safety of RLS drugs
to be assessed in multiple ways, promoting
treatment that is individualized for each patient.

randomized, double-blind study. Sleep
Medicine., 16, 181-185, 2015.
10）Ma JF, Wan Q, Hu XY et al.: Eﬃcacy andsafety of pramipexole in chinese patientswith restless legs syndrome : Result from aConﬂict of interest
The authors declare no conﬂicts of interest.

multi-center, randomized, double-blind,placebo-controlled trial. Sleep Medicine., 13,
58-63 2012.

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