CRD summary

The authors concluded that dopamine agonists were significantly more efficacious than placebo for treatment of restless leg syndrome. The authors’ conclusions appeared to reflect the evidence, but the limited search may have weakened the evidence.

Authors' objectives

To evaluate the efficacy and tolerability of dopamine agonists for the treatment of restless leg syndrome.

Searching

PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) were searched before August 2009 for peer-reviewed articles published in English. Search terms were reported. Reference lists in retrieved articles were screened. Abstracts were excluded.

Study selection

Randomised controlled trials (RCTs) were eligible if they compared at least one dopamine agonist drug with placebo in adults (aged >18 years) with restless leg syndrome diagnosed using valid published criteria. Studies had to assess outcomes using International Restless Leg (IRLS) Study Group Rating Scale or Clinical Global Impressions-Improvement (CGI-I) scale, have more than 10 participants in each treatment arm and present sufficient data to permit calculation of a treatment effect and its variance. The review evaluated tolerability by assessing adverse events. Studies of bromocriptine and lisuride were excluded.

The included studies compared pramipexole, ropinirole, rotigotine, carbergoline, sumanirole and pergolide with placebo. Some studies used a variable dosage regimen. All of the studies were in patients with primary restless leg syndrome. Most patients had been previously treated for this condition. All had been diagnosed using valid criteria. Disease duration ranged from three to 24 years across treatment groups. The mean age of participants ranged from 50 to 60 years. Males were in the minority in most treatment arms. Where reported, most studies were in white patients.

Two reviewers independently selected studies and resolved disagreements by consensus.

Assessment of study quality

Validity was assessed using 17 items of the CONSORT statement with the focus on items in the methods and results sections. Criteria assessed participants, interventions, objectives, outcome and estimation, sample size, randomisation, blinding, statistical methods, participant flow, numbers analysed, analyses and adverse events.

The authors did not state how many reviewers assessed validity.

Data extraction

Two reviewers independently extracted the mean change and 95 % confidence interval (CI) from baseline between treatment and placebo groups in IRLS scores and the relative risk (RR) of response defined as a CGI-I score of 1 or 2 (very much or much improved).

Methods of synthesis

Where more than two studies provided data, pooled weighted mean differences (WMD) with 95 % CIs of differences in IRLS scores and pooled relative risks with 95% CIs of differences in response rates were calculated using a random-effects model. Heterogeneity was assessed using the Q statistic and quantified using the I² statistic. Sensitivity analyses were conducted to explore the effects of excluding specific studies. Pooled proportions of adverse events with 95% CIs were calculated using a random-effects model. Where more than three studies provided data, cumulative meta-analysis was used to examine the treatment effect over time. Meta-regression was used to examine the influence of baseline IRLS score. The possibility of publication bias was explored using Egger’s test.

Results of the review

Eighteen double-blind RCTs were included (n=2,868 patients, range 133 to 359).

All studies reported nine of the 17 items on the CONSORT checklist. Withdrawal rates ranged from 2% to 47%. Treatment duration ranged from one to 36 weeks.

Pramipexole (six studies, n=1,019 patients) was associated with a significant improvement in IRLS score (WMD -6.63, 95% CI -9.15 to -4.10) and a significant increase in response rate (RR 1.70, 95% CI 1.41 to 2.04). Significant heterogeneity was found for the analysis of IRLS score (I²=76%).

Ropinirole (five studies, n=1,212 patients) was associated with a significant improvement in IRLS score (WMD -3.64, 95% CI -4.76 to -2.51) and a significant increase in response rate (RR 1.39, 95% CI 1.27 to 1.53). No significant heterogeneity was found for either analysis.

Rotigotine (three studies, n=365 patients) was associated with a significant improvement in IRLS score (WMD -5.62, 95% CI -7.64 to -3.60) and a significant increase in response rate (RR 1.49, 95% CI 1.18 to 1.88). No significant heterogeneity was found for either analysis.

Carbergoline (two studies, n=83 patients) was associated with a significant improvement in IRLS score (WMD -12.4, 95% CI -18.3 to -6.60). One study found a significant increase in response rate (RR 2.67, 95% CI 1.62 to 4.39). No significant heterogeneity was found.

Sumanirole (one study, n=106 patients) was associated with a significant improvement in IRLS score (MD -3, 95% CI -5.57 to -0.43) and a non-significant increase in response rate (RR 1.11, 95% CI 0.86 to 1.41).

Pergolide (one study, n=83 patients) was associated with a significant improvement in IRLS score (WMD -10.4, 95% CI -14.6 to -6.22).

Pramipexole was associated with a significantly greater improvement in IRLS score and response rate than ropinirole. There was no significant difference between pramipexole and rotigotine in either outcome.

There was no evidence of publication bias from Egger’s test. Results of sensitivity analyses were reported.

Pooled proportions of patients with adverse events were pramipexole (4.8%, 95% CI 2.0% to 8.7%, I²=67%), ropinirole (10.2%, 95% CI 2.6% to 22.1%, I²=94%) and rotigotine (7.6%, 95% CI 1.3 to 18.5%; I²=77%). Significant heterogeneity was found for all these analyses.

Authors' conclusions

Dopamine agonists were significantly more efficacious than placebo for treatment of restless leg syndrome.

CRD commentary

The review question was clearly stated and inclusion criteria were appropriately defined. The search was limited to two databases plus references and no attempts were made to minimise publication and language biases. This may have led to omission of relevant studies. Potential for publication bias was assessed and none was found. Validity was assessed and results were reported. Methods were used to minimise reviewer errors and bias in study selection and data extraction; it was unclear whether similar steps were taken in the validity assessment. It was not clear whether analyses were on an intention-to-treat (ITT) basis; given the relatively high drop-out rate in some studies use of ITT or not may have influenced results. Appropriate methods were used for the meta-analyses, heterogeneity was assessed and various analyses conducted to examine potential sources of heterogeneity.

Much of the review was well-conducted. The authors’ conclusions appeared to reflect the evidence, but the limited search may have weakened the evidence.

Implications of the review for practice and research

Practice: The authors reported that other reviewers had stated that pergolide and cabergoline were not recommended as first-line treatment for restless leg syndrome as they required monitoring due to an increased risk of cardiac valvular fibrosis.

Research: The authors stated that RCTs were required to directly compare different dopamine agonists for treatment of restless leg syndrome. Future studies should take account of the substantial placebo effect when estimating the required sample size.

Funding

Not stated.

Bibliographic details

Zintzaras E, Kitsios GD, Papathanasiou AA, Konitsiotis S, Miligkos M, Rodopoulou P, Hadjigeorgiou GM. Randomized trials of dopamine agonists in restless legs syndrome: a systematic review, quality assessment, and meta-analysis. Clinical Therapeutics 2010; 32(2): 221-237. [PubMed: 20206780]

Original Paper URL

http://dx.doi.org/10.1016/j.clinthera.2010.01.028

Indexing Status

Subject indexing assigned by NLM

MeSH

Aged; Dopamine Agonists /administration & dosage /adverse effects /therapeutic use; Evidence-Based Medicine; Female; Humans; Male; Middle Aged; Placebo Effect; Randomized Controlled Trials as Topic; Restless Legs Syndrome /diagnosis /drug therapy; Risk Assessment; Treatment Outcome

AccessionNumber

12010002242

Database entry date

18/05/2011

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.