|EFNS guidelines on management of restless legs syndrome and periodic limb movement disorder in sleep
|Vignatelli L, Billiard M, Clarenbach P, Garcia-Borreguero D, Kaynak D, Liesiene V, Trenkwalder C, Montagna P
The authors concluded that level A recommendations support the use of cabergoline, gabapentin, pergolide, ropinirole, and short-term levodopa and transdermal rotigotine for primary restless leg syndrome. The evidence appears to support the authors’ conclusions, but the poor reporting of review methods makes it difficult to comment on the reliability of these conclusions.
To evaluate the effectiveness of treatments for restless leg syndrome (RLS) and periodic limb movement disorder (PLMD) in sleep.
MEDLINE, EMBASE, CINAHL and the Cochrane Library were searched from inception to 2004; the search terms were reported. In addition, existing guidelines and reference lists in identified studies were screened. Details of the search strategy were provided in supplementary tables available on the European Journal of Neurology website (accessed 08/07/08; a subscription may be required for access).
Studies that evaluated the effectiveness and maintained effect of any drugs or physical treatment for patients with RLS or PLMD were eligible for inclusion. Explicit diagnostic criteria were not required for RLS and PLMS, and patients could have other co-morbidity or co-treatment.
The review evaluated the following drug classes: adrenoreceptors, antiepileptics, benzodiazepines/hypnotics, dopaminergic agents, opioids and other treatments.
For RLS, the review outcomes were paraesthesia/dysaesthesia or pain, polysomnographic indices of sleep dysfunction, quality of life, adverse effects and augmentation effect, drop-outs and patient preference for continuation of treatment. For PLMD, the review outcomes were polysomnographic indexes of sleep dysfunction, quality of life, adverse effects and drop-outs.
The authors did not state how the papers were selected for the review, or how many reviewers performed the selection.
Assessment of study quality
Studies were classified using the hierarchy of evidence described by the EFNS Task Force (see Other Publications of Related Interest). The studies were graded from 1 (highest class of evidence) to IV (lowest class of evidence). It appears that all members of the task force classified the studies, and any disagreements were resolved through discussion. Only evidence from class I, II and III studies was referred to in the review.
The level of evidence for each treatment was graded using the hierarchy of evidence described by the EFNS Task Force Guidelines (grade A for the highest level).
The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction. For each study, measures of treatment effect were presented together with adverse effects.
Methods of synthesis
The studies were combined in a narrative, grouped by drug type.
Results of the review
Only evidence about interventions supported by level A recommendations is reported below.
Adrenoreceptors were evaluated in 15 studies, antiepileptics in 22 studies, benzodiazepines/hypnotics in 36 studies, levodopa in 52 studies, ergot derivatives in 39 studies, non-ergot derivatives in 39 studies, opioids in 22 studies and other treatments in 82 studies.
The most common methodological flaws included inadequate allocation concealment, lack of predefined end points and use of non-validated or surrogate outcomes.
Levodopa (52 studies): there was level A evidence that levodopa was effective in reducing symptoms of RLS in primary RLS and at short-term follow-up (one class I study and seven short-term class II studies), and in improving sleep quality and quality of life and reducing PLMS (three class II studies). Commonly reported adverse effects included diarrhoea, nausea, dyspepsia, reduced general drive, muscle weakness, somnolence and headache; adverse effects were minor but more common than with placebo.
Ergot derivatives (39 studies): there was level A evidence that pergolide (one class I study with long term class III follow-up) and cabergoline (one class I study and one class III long-term follow-up study) were effective in primary RLS. Most frequent ergot-related adverse effects were controlled by domperidone.
Non-ergot derivatives (39 studies): there was level A evidence that oral ropinirole (four class I studies) and transdermal ropinirole (one class I study) were effective in primary RLS. Adverse effects were similar to other dopaminergic agents.
Antiepileptics (22 studies): there was level A evidence that gabapentine (one class I study and four class III studies) was effective in primary RLS. Adverse effects were usually mild and reversible.
Other treatments: there was level A evidence that transdermal oestrogen was not effective in PLMD (one class I study). Many other results were also reported.
Level A recommendations supporting the use of cabergoline, gabapentin, pergolide, ropinirole, and short-term levodopa and transdermal rotigotine for primary RLS can be made. There was level A evidence that transdermal oestrogen was not effective in PMLD.
The review question was defined with respect to the participants and outcomes. Inclusion criteria for the intervention and study design were broad. Several relevant sources were searched but no attempts to minimise either publication or language bias were reported. The methods used to select studies and extract the data were not described, so it is not known whether any efforts were made to reduce reviewer error and bias. Study validity was assessed using a hierarchy of evidence approach that makes it difficult to comment on the reliability of the evidence presented. The use of a narrative synthesis was appropriate in view of the diversity of the studies, and the synthesis broadly took account of study quality. The evidence appears to support the authors’ conclusions, but the lack of clear reporting of review methods makes it difficult to comment on their reliability.
Several of the review authors have connections with pharmaceutical companies.
Implications of the review for practice and research
Practice: The authors made the following recommendations for primary RLS.
Carbergoline (0.5 to 2 mg once daily) improves RLS scores.
Gabapentin (800 to 1,800 mg daily) reduces RLS scores and improves sleep efficiency in PLMS-I ('periodic limb movement in sleep').
Levodopa/benserazide (mean dose 159/40 mg at bedtime) improves RLS symptoms, quality of sleep, sleep latency, PLMS-I and quality of life.
Pergolide (mean dose 0.4 to 0.55 mg/day) reduces RLS severity and improves quality of sleep.
Ropinirole (mean dose 1.5 to 4.6 mg/day) improves RLS scale scores, quality of life, sleep latency and PLMS-I/PLMS-A.
Transdermal rotigotine (4.5 mg) improved RLS in the short term.
For PLMD, transdermal oestrogen is not effective.
Research: The authors stated the need for good-quality trials evaluating treatments for RLS during pregnancy and childhood.
Vignatelli L, Billiard M, Clarenbach P, Garcia-Borreguero D, Kaynak D, Liesiene V, Trenkwalder C, Montagna P. EFNS guidelines on management of restless legs syndrome and periodic limb movement disorder in sleep. European Journal of Neurology 2006; 13(10): 1049-1065
Other publications of related interest
Brainin M, Barnes M, Baron JC, Gilhus NE, Hughes R, Selmaj K, et al. Guidance for the preparation of neurological management guidelines by EFNS scientific task forces - revised recommendations. Eur J Neurol 2004;11:577-81.
Subject indexing assigned by NLM
Advisory Committees /standards; Anticonvulsants /pharmacology /therapeutic use; Disease Management; Dopamine Agents /pharmacology /therapeutic use; Europe; Humans; Nocturnal Myoclonus Syndrome /drug therapy /physiopathology; Restless Legs Syndrome /drug therapy /physiopathology; Sleep /drug effects /physiology
Date bibliographic record published
Date abstract record published
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.