Interventions for chronic kidney disease‐associated restless legs syndrome

Seerapani Gopaluni; Mohamed Sherif; Naim A Ahmadouk

doi:10.1002/14651858.CD010690.pub2

. 2016 Nov 7;2016(11):CD010690. doi: 10.1002/14651858.CD010690.pub2

Interventions for chronic kidney disease‐associated restless legs syndrome

Seerapani Gopaluni ^1,^2,^✉, Mohamed Sherif ², Naim A Ahmadouk ³

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC6464953 PMID: 27819409

Abstract

Background

Restless legs syndrome (RLS) is defined as the spontaneous movement of the limbs (mainly legs) associated with unpleasant, sometimes painful sensation which is relieved by moving the affected limb. Prevalence of RLS among people on dialysis has been estimated between 6.6% and 80%. RLS symptoms contribute to impaired quality of life and people with RLS are shown to have increased cardiovascular morbidity and mortality.

Various pharmacological and non‐pharmacological interventions have been used to treat primary RLS. However, the evidence for use of these interventions in people with chronic kidney disease (CKD) is not well established. The agents used in the treatment of primary RLS may be limited by the side effects in people with CKD due to increased comorbidity and altered drug pharmacokinetics.

Objectives

The aim of this review was to critically look at the benefits, efficacy and safety of various treatment options used in the treatment of RLS in people with CKD and those undergoing renal replacement therapy (RRT). We aimed to define different group characteristics based on CKD stage to assess the applicability of a particular intervention to an individual patient.

Search methods

We searched the Cochrane Kidney and Transplant Specialised Register to 12 January 2016 through contact with the Information Specialist using search terms relevant to this review.

Selection criteria

Randomised controlled trials (RCT) and quasi‐RCTs that assessed the efficacy of an intervention for RLS in adults with CKD were eligible for inclusion. Studies investigating idiopathic RLS or RLS secondary to other causes were excluded.

Data collection and analysis

Two authors independently assessed studies for eligibility and conducted risk of bias evaluation. Results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes.

Main results

We included nine studies enrolling 220 dialysis participants. Seven studies were deemed to have moderate to high risk of bias. All studies were small in size and had a short follow‐up period (two to six months). Studies evaluated the effects of six different interventions against placebo or standard treatment. The interventions studied included aerobic resistance exercise, gabapentin, ropinirole, levodopa, iron dextran, and vitamins C and E (individually and in combination).

Aerobic resistance exercise showed a significant reduction in severity of RLS compared to no exercise (2 studies, 48 participants: MD ‐7.56, 95% CI ‐14.20 to ‐0.93; I² = 65%), and when compared to exercise with no resistance (1 study, 24 participants: MD ‐11.10, 95% CI ‐17.11 to ‐5.09), however there was no significant reduction when compared to ropinirole (1 study, 22 participants): MD ‐0.55, 95% CI ‐6.41 to 5.31). There were no significant differences between aerobic resistance exercise and either no exercise or ropinirole in the physical or mental component summary scores (using the SF‐36 form). Improvement in sleep quality varied. There was no significant difference in subjective sleep quality between exercise and no exercise; however one study reported a significant improvement with ropinirole compared to resistance exercise (MD 3.71, 95% CI 0.89 to 6.53). Using the Epworth Sleepiness Scale there were no significant differences between resistance exercise and no exercise, ropinirole, or exercise with no resistance. Two studies reported there were no adverse events and one study did not mention if there were any adverse events. In one study, one patient in each group dropped out but the reason for dropout was not reported. Two studies reported no adverse events and one study did not report adverse events.

Gabapentin was associated with reduced RLS severity when compared to placebo or levodopa, and there was a significant improvement in sleep quality, latency and disturbance reported in one study when compared to levodopa. Three patients dropped out due to lethargy (2 patients), and drowsiness, syncope and fatigue (1 patient).

Because of a short duration of action, rebound and augmentation were noted with levodopa treatment even though it conferred some benefit in reducing the symptoms of RLS. Reported adverse events were severe vomiting, agitation after caffeine intake, headaches, dry mouth, and gastrointestinal symptoms.

One study (25 participants) reported iron dextran reduced the severity of RLS at weeks one and two, but not at week four. Vitamins C, E and C plus E (1 study, 60 participants) helped the symptoms of RLS with minimal side effects (nausea and dyspepsia) but more evidence is needed before any conclusions can be drawn.

Authors' conclusions

Given the small size of the studies and short follow‐up, it can only be concluded that pharmacological interventions and intra‐dialytic exercise programs have uncertain effects on RLS in haemodialysis patients. There have been no studies performed in non‐dialysis CKD, peritoneal dialysis patients, or kidney transplant recipients. Further studies are warranted before any conclusions can be drawn. Aerobic resistance exercise and ropinirole may be suitable interventions for further evaluation.

Plain language summary

Interventions for treating restless legs syndrome in patients with chronic kidney disease

What is the issue?

People with restless legs syndrome (RLS) have an irresistible urge to move their limbs to relieve themselves of unpleasant sensations. RLS is common in chronic kidney disease (CKD) patients, however the cause is unknown. Patients with RLS often have reduced quality of life and increased risk of developing heart disease.

Medications such as dopamine agonists, benzodiazepines, anti‐epileptics, iron and non‐pharmacological agents such as exercise that were used to treat primary RLS were also used to treat RLS in CKD patients. However, these agents may be unsuitable to CKD patients due to associated co‐morbidity and altered pharmacokinetics in CKD patients.

What did we do?

We searched Cochrane Kidney and Transplant's Specialised Register to 12 January 2016. Nine studies reported enrolling 220 stable, adult haemodialysis patients of both sexes, were included in the review.

What did we find?

The quality of the studies was deemed to be moderate. Of the nine studies, one was sponsored by a pharmaceutical company and funding sources were reported for only two other studies. The included studies were heterogeneous, small in size and had short follow‐up periods.

The interventions studied included exercise, gabapentin, ropinirole, levodopa, iron dextran, and vitamins C and E (individually and in combination). All interventions reduced the severity of RLS compared to a control. Intradialytic aerobic exercise reduced the severity of RLS however the safety of this intervention is unclear. Resistance exercise did not improve sleep quality but improved the mental health component on a quality of life questionnaire. This improvement in mental health component was not significant when compared to no exercise or ropinirole. Ropinirole reduced the symptoms of RLS and improved quality of sleep without any reported side effects. Gabapentin and levodopa improved the symptoms of RLS; however there were several adverse events reported included lethargy, drowsiness and fatigue for gabapentin, and vomiting, agitation, headaches, dry mouth, and gastrointestinal symptoms for levodopa. Iron dextran infusion reduced the symptoms of RLS but was only significant up to two weeks after treatment. Vitamin C, E and their combination also reduced RLS symptoms with minimal side effects. Small size and short duration of follow‐up were the major drawbacks of these studies.

Conclusions

The small number of studies, small sample sizes and short duration of follow up make it difficult to draw any firm conclusions. The effects of aerobic exercise and other pharmacological agents on RLS are uncertain in haemodialysis patients. There is a need to perform high quality randomised studies to establish the best treatment for RLS in patients with CKD. Aerobic exercise and ropinirole may be suitable interventions for further evaluation.

Background

Description of the condition

The symptoms of restless legs syndrome (RLS) were first described in 1672 by Sir Thomas Willis. It is defined as the spontaneous movement of the limbs (mainly legs) associated with unpleasant, sometimes painful sensation and relieved by moving the affected limb. This definition has not been significantly modified since it was first defined in 1945 (Ekbom 1945).

Diagnostic criteria for RLS was published by the International Restless Legs Syndrome Study Group (IRLSSG) in 1995 (Walters 1995) and were subsequently revised by the National Institute of Health consensus conference in 2002 (Allen 2003) to include the following.

Urge to move the legs usually with unpleasant sensations in the legs; arms and other body parts are occasionally involved
Symptoms begin or worsen during periods of rest or inactivity
Symptoms partially or totally relieved by movement and as long as the activity continues
Symptoms are worse during the evening or night than during the day.

In addition, separate modified criteria were established for diagnosing RLS in special populations, for RLS augmentation, and for assessment of RLS in epidemiologic studies.

Prevalence of RLS in the general population is 5% to 15% whereas the prevalence in dialysis patients is 6.6% to 80% (Al‐Jahdali 2009). RLS contributes to impaired quality of life (QOL) (Mucsi 2005) and patients with RLS have increased cardiovascular morbidity and mortality (La Manna 2011).

Description of the intervention

There is emerging evidence with strong recommendations advocating the use of various agents to treat primary RLS. Dopaminergic agents have been established as first line treatment options for primary RLS. Anti‐epileptic drugs, benzodiazepines, opiates, alpha‐adrenergic blockers, iron supplementation, aerobic exercise, and Botox have been used in the treatment of people with primary RLS (Agarwal 2011; Giannaki 2010; Hornyak 2014).

However, the evidence for use of these agents in people with chronic kidney disease (CKD) is not well established. The usual agents that have been tried in the treatment of primary RLS may be limited by the side effects in people with CKD.

Kidney impairment can alter drug pharmacokinetics and pharmacodynamics, and consequently people with kidney impairment are at risk of developing adverse effects. People with CKD need to take many drugs and are at high risk for drug interactions and drug‐related problems (Manley 2003).

How the intervention might work

Advanced brain imaging techniques have implicated dysfunction of subcortical areas as causative in primary RLS.

Iron deficiency is considered to be common in primary RLS and there is an inverse relation between iron levels and the severity of RLS symptoms (Sun 1998). Abnormality of the body's ability to use and store iron may lead to the dopamine dysfunction. Iron probably works by both improving anaemia as well as being a cofactor for tyrosine hydroxylase, a rate limiting step in dopamine production pathway in the nigrostriatal area (Sloand 2004).

Evidence for the hypothesis implicating dopaminergic dysfunction as a cause for RLS came from the chance finding of symptom relief on small doses of levodopa (Akpinar 1982) and exacerbation of symptoms with dopamine antagonists (Winkelmann 2001). Dopamine agonists directly stimulate dopamine receptors and are generally superior to levodopa in treating RLS.

The pathophysiology of RLS in people with CKD is not well understood. Inadequate dialysis leading to toxin accumulation, iron deficiency, hyperparathyroidism and high calcium and phosphate levels have been implicated in the pathogenesis by various studies. Most drug interventions used for people with CKD have been extrapolated from experience in treating people with primary RLS. Some interventions specific to those with CKD have been tried based on anecdotal evidence.

Dopamine pathways have been implicated in the pathophysiology of RLS for a long time. It is known that iron is involved in a rate‐limiting step required to convert tyrosine to levodopa that is later decarboxylated to dopamine. Correcting functional iron deficiency using iron supplementation may help reduce the symptoms of RLS in haemodialysis patients.
Gabapentin (an anticonvulsant) has been shown to help RLS in non‐uraemic patients (Lee 2016). This drug is excreted by the kidney (77%) and has a long‐half lifetime. Gabapentin modulates various receptor sites and alters dopamine, serotonin and norepinephrine release.
Levodopa was shown to be beneficial in ameliorating the symptoms from RLS in non‐uraemic patients. However it has adverse effects of rebound, augmentation and tolerance to beneficial effects.
Ropinirole is a synthetic dopamine agonist with relatively large D3 and D4 affinity. Because of its short plasma half‐life and liver metabolism it may be safer to use in patients with kidney failure.
High oxidative stress has been implicated in pathogenesis of RLS and the use of anti‐oxidants vitamin C and E may relieve the symptoms of RLS.

Why it is important to do this review

Abnormal limb movement disorders that affect sleep, such as periodic limb movement disorder and RLS, are reported to be common among people with CKD and those undergoing dialysis (Kavanagh 2004). These disorders, which are often both under‐recognised and treated, are thought to cause significant sleep disruption and reduce QOL (Mucsi 2005). As well as experiencing poor QOL, mounting evidence suggests people with disturbed sleep patterns are also at increased risk of developing hypertension and cardiovascular diseases (Walters 2010).

In view of the coexistence of RLS with other sleep disturbances in people with kidney disease, it is difficult to identify people with RLS alone. It has only been in the last 15 years that diagnostic criteria were agreed internationally and are being used to identify participants for inclusion in therapeutic studies.

The available evidence concerning treatment of RLS in the context of kidney impairment is limited, and the best options to treat these patients remain unclear.

Objectives

The aim of this review was to critically look at the benefits and safety of various treatment options used in the treatment of RLS in people with CKD and those undergoing RRT. We aimed to define different group characteristics based on CKD stage to assess the applicability of particular interventions to individual patients.

Methods

Criteria for considering studies for this review

Types of studies

All RCTs and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods), looking at the specified therapeutic interventions for people with RLS associated with CKD stages 3 to 5, including different modes of RRT were included.

Types of participants

Inclusion criteria

All RCTs that recruited adults of both sexes over the age of 18 years with CKD stages 3 to 5 with secondary RLS as diagnosed using the criteria set out by the IRLSSG were eligible for inclusion. Patients undergoing peritoneal dialysis or haemodialysis, and those who had received a kidney transplant were included.

Exclusion criteria

Idiopathic RLS
RLS secondary to other causes (e.g. diabetes, amyloid)
RLS predating onset of kidney disease.

People with diagnoses of periodic limb movement disorders not specifically diagnosed as RLS were excluded from our analyses.

Types of interventions

Non‐pharmacological interventions not related to renal replacement therapy (RRT) including exercise, smoking cessation and alcohol intake reduction
Pharmacological interventions (of any dose, combination, duration) versus placebo, no treatment, or other pharmacological agent. The following agents were included.
- Iron/erythropoietic stimulating agents to adequately treat anaemia
- Benzodiazepines: clonazepam, diazepam
- Dopamine agonists: ropinirole, pramipexole, pergolide, cabergoline
- Antiepileptics: gabapentin, pregabalin
- Other medications/treatments: vitamins, minerals, nutritional supplements
Any other intervention that was found to be relevant such as changes to dialysis regimens, kidney transplantation, enhancing dialysis adequacy and optimising electrolyte balance.

Types of outcome measures

Reduction in symptoms and signs, assessed by questionnaires (International RLS Scale, Johns Hopkins RLS Severity Scale) or by objective testing (Suggested Immobilisation Test (SIT) and actigraphy)
Reduction in sleep disturbances related to RLS, assessed by questionnaires (RLS‐6 scale, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS)) or by objective testing (actigraphy)
Adverse events related to interventions.

Each of the interventions described may relate to subsets of participants, depending on the stage of CKD, underlying diagnoses, RRT mode and demographic variables. Applicability was assessed by analysing studies for particular patient group characteristics and adverse events relating to specific interventions in that group.

Primary outcomes

The effects of interventions in reducing symptom severity due to RLS in people with CKD and potential complications related to the use of such interventions.

Secondary outcomes

Improvement in QOL
Improvement in quality of sleep
Reduction in cardiovascular mortality
Applicability to individual patients.

Search methods for identification of studies

Electronic searches

We searched Cochrane Kidney and Transplant Specialised Register (to 12 January 2016) through contact with the Information Specialist using search terms relevant to this review. The Specialised Register contains studies identified from the following sources.

Quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
Weekly searches of MEDLINE OVID SP
Handsearching of kidney‐related journals and the proceedings of major kidney conferences
Searching of the current year of EMBASE OVID SP
Weekly current awareness alerts for selected kidney journals
Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Specialised Register were identified through search strategies for CENTRAL, MEDLINE, and EMBASE, based on the scope of Cochrane Kidney and Transplant. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about the Cochrane Kidney and Transplant.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

Reference lists of review articles, relevant studies, and clinical practice guidelines.
Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Data collection and analysis

Selection of studies

The search strategy described was used to obtain titles and abstracts that were relevant to the review. Titles and abstracts were screened independently by two authors, who discarded studies that were not applicable; however studies and reviews that included relevant data or information on studies were retained initially. Two authors independently assessed the retrieved abstracts, and where necessary assessed the full text of these studies to determine which satisfied the inclusion criteria.

Data extraction and management

Data extraction was carried out independently by two authors using standard data extraction forms. Studies reported in non‐English language journals were translated before assessment. Where more than one publication of one study existed, records were grouped together and the publication with the most complete data was included. Where relevant, outcome data that were only published in earlier versions was used. Disagreements were resolved by consultation with all authors.

Assessment of risk of bias in included studies

The following items were independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).

Was there adequate sequence generation (selection bias)?
Was allocation adequately concealed (selection bias)?
Was knowledge of the allocated interventions adequately prevented during the study?
- Participants and personnel (performance bias)
- Outcome assessors (detection bias)
Were incomplete outcome data adequately addressed (attrition bias)?
Were reports of the study free of suggestion of selective outcome reporting (reporting bias)?
Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

Where continuous scale of measurements was used to assess the effects of treatment (improvement in the sleeping score, improvement in the international restless leg syndrome scale score, improvement in Johns Hopkins RLS Severity Scale score), the mean difference (MD) was used, or the standardised mean difference (SMD) when different scales were used.

Dealing with missing data

We attempted to contact study authors to obtain missing data.

We calculated the standard deviations when not reported and data were available either in the paper or provided by study authors.

Assessment of heterogeneity

Duration of treatment, dose and form of drugs were assessed to ensure there was no heterogeneity. Non‐pharmaceutical interventions (e.g. the form and frequency of exercise) were also assessed to ensure there was no heterogeneity.

Where applicable, heterogeneity was analysed using a Chi² test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.

Duration of treatment, dose and form of drugs, and follow‐up period were assessed to determine heterogeneity.

Non‐pharmaceutical interventions (e.g. the form and frequency of exercise) and follow‐up period were assessed to determine heterogeneity.

Assessment of reporting biases

We did not identify sufficient numbers of RCTs to examine for publication bias using funnel plots (Higgins 2011).

Data synthesis

Data were to be pooled using the random‐effects model but the fixed‐effect model was also to be used to ensure robustness of the model chosen and susceptibility to outliers. Data were not pooled due to significant heterogeneity identified in outcomes measured.

Subgroup analysis and investigation of heterogeneity

We planned subgroup analysis to explore possible sources of heterogeneity (e.g. participants, interventions and study quality). Heterogeneity among participants could be related to age (e.g. less than 65 years versus more than 65 years old), renal pathology (for example diabetic kidney disease, glomerulonephritis, renovascular disease, polycystic kidney disease). Heterogeneity in treatments could be related to prior agent(s) used and the agent, dose and duration of therapy.

Subgroup analysis was not done due to limited number of studies investigating the effect of a particular intervention. Adverse events were tabulated and assessed with descriptive techniques, as they were different for the various agents used.

Sensitivity analysis

We planned to perform sensitivity analyses in order to explore the influence of the following factors on effect size.

Repeating the analysis excluding unpublished studies
Repeating the analysis taking account of risk of bias, as specified
Repeating the analysis excluding any very long or large studies to establish how much they dominate the results
Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country.

We were unable to perform sensitivity analysis due to insufficient numbers of studies in each intervention category.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification

Results of the search

The searches returned 29 records. After grouping these records into studies (22 studies), nine studies (11 records) were excluded after full‐text review and nine studies (14 records) were included in the analyses. Four recently completed studies will be assessed in a future update of this review (NCT00996944; NCT01537042; NCT02011191; Razazian 2015) (Figure 1).

Included studies

We included nine studies that involved 220 participants undergoing RRT (Giannaki 2013; Giannaki 2013a; Micozkadioglu 2004; Mortazavi 2013; Pellecchia 2004; Sagheb 2012; Sloand 2004; Thorp 2001; Trenkwalder 1995). Eight studies only enrolled haemodialysis patients and one study enrolled haemodialysis and peritoneal dialysis patients (Sloand 2004) (Characteristics of included studies).

We contacted the authors for either missing data or clarification of the reported data; one author responded to our request.

Design

All nine studies were RCTs. Four studies were crossover studies (Micozkadioglu 2004; Pellecchia 2004; Thorp 2001; Trenkwalder 1995). Eight of the studies involved two comparisons whilst one (Sagheb 2012) included four groups for comparison. Three studies were open‐labelled studies (Micozkadioglu 2004; Mortazavi 2013; Pellecchia 2004), one was single blinded (Giannaki 2013a), and the other five were double‐blind (Giannaki 2013; Sagheb 2012; Sloand 2004; Thorp 2001; Trenkwalder 1995).

Sample sizes

Studies included within this review were relatively small in size, varying from 11 to 60 participants.

Setting

Studies were conducted in dialysis centres located in a number of countries and may reflect inherent variations in treatment and clinical practices. Study countries included Greece (Giannaki 2013; Giannaki 2013a); Iran (Mortazavi 2013; Sagheb 2012); USA (Sloand 2004; Thorp 2001); Germany (Trenkwalder 1995); Italy (Pellecchia 2004), and Turkey (Micozkadioglu 2004).

Participants

Participants were diagnosed with RLS based on criteria proposed by the IRLSSG. Updated IRLSSG standard criteria for RLS (Allen 2003) were used to identify participants for inclusion into the studies in all but two (Trenkwalder 1995, Thorp 2001). However criteria used by both studies were very similar to IRLSSG and were included in this review.

Interventions

Distinctly different interventions were assessed in the included studies.

Exercise interventions
- Aerobic exercise versus no exercise (Mortazavi 2013)
- Resistance exercise with either ropinirole or exercise with no resistance (Giannaki 2013a).
Pharmacological agents
- Levodopa versus placebo (Trenkwalder 1995)
- Gabapentin versus placebo (Thorp 2001)
- Gabapentin versus levodopa (Micozkadioglu 2004)
- Ropinirole versus levodopa (Pellecchia 2004)
- Iron dextran versus placebo (Sloand 2004)
- Vitamin C, vitamin E and placebo in four different combinations (Sagheb 2012).

Outcomes

The primary outcome in all studies was change in RLS severity from baseline to study end. Changes in QOL and sleep were included in the review when reported. None of the studies reported data on cardiovascular morbidity and mortality.

RLS severity was measured using different rating scales. Thorp 2001 and Trenkwalder 1995 pre‐dated publication of the validated IRLSSG RLS severity scoring tool which includes 10 questions each with five options scored from 0 to 4, giving a maximum score of 40. Four studies used this as the scoring tool (Giannaki 2013; Giannaki 2013a; Mortazavi 2013; Sagheb 2012). Micozkadioglu 2004 and Pellecchia 2004 applied a six question‐based IRLSSG scoring tool (introduced before the current IRLSSG tool) with a maximum score of 24. Three studies used their own non‐validated scoring tools (Thorp 2001; Trenkwalder 1995; Sloand 2004).

QOL was measured using validated SF‐36 questionnaire in three studies (Giannaki 2013; Micozkadioglu 2004; Mortazavi 2013). Trenkwalder 1995 used 13 visual analogue scales, each measuring different QOL components.

Sleep quality was assessed and reported in five studies using tools such as PSQI and ESS (Giannaki 2013; Giannaki 2013a; Micozkadioglu 2004; Pellecchia 2004; Trenkwalder 1995).

Adverse events were reported in all but one study (Mortazavi 2013) (Table 1).

1. Adverse events.

Study	Intervention: number of events	Comments	Control: number of events	Comments
Giannaki 2013	Resistance exercise: 0/16	No adverse events	No exercise: 0/16	No adverse events
Giannaki 2013a	Exercise with no resistance: 0/12	No adverse events	Exercise with no resistance: 0/12	No adverse events
Mortazavi 2013	Exercise: not reported	Not reported	No exercise: not reported	Not reported
Thorp 2001	Gabapentin: 2/15	Withdrawal due to lethargy in gabapentin group.	Placebo: 1/16	Myocardial infarction in placebo group prior to receiving gabapentin
Micozkadioglu 2004	Gabapentin: 1/15	Withdrawal due to fatigue, syncope in gabapentin group	Levodopa: not reported	Not reported
Trenkwalder 1995	Levodopa: adverse effects were pooled and not reported separately for dialysis patients	Adverse effects were pooled and not reported separately for dialysis patients	Placebo: adverse effects were pooled and not reported separately for dialysis patients.	Adverse effects were pooled and not reported separately for dialysis patients.
Pellecchia 2004	Ropinirole: 0/13	No adverse events	Levodopa: 1/13	Withdrawal due to vomiting in levodopa group
Sloand 2004	Iron dextran: 2/11 had nausea/vomiting & 2/11 had headaches	Nausea/vomiting Headache	IV saline: 3/14 had nausea	Nausea
Sagheb 2012	Vitamin C & E, vitamin C & placebo, vitamin E & placebo: 3/45 had nausea 3/45 had dyspepsia	Nausea Dyspepsia	Placebo: 1/15 had nausea	Nausea

Database	Search terms
CENTRAL	(restless next leg):ti,ab,kw (ekbom next syndrome):ti,ab,kw (periodic next leg next movement):ti,ab,kw (periodic next limb next movement):ti,ab,kw (PLM or PLMS):ti,ab,kw ((uremic next polyneuropath) or (uremic next neuropath) or (peripheral next polyneuropath)):ti,ab,kw ((nocturnal next movement) or (nocturnal next leg next movement) or (nocturnal next limb next movement)):ti,ab,kw (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7) (renal next replacement next therapy):ti,ab,kw dialysis:ti,ab,kw (hemodialysis or hemodiafiltration or hemofiltration):ti,ab,kw (CAPD or CCPD or APD):ti,ab,kw ((kidney or renal) next disease):ti,ab,kw ((kidney or renal) next failure):ti,ab,kw (CKF or CKD or CRF or CRD):ti,ab,kw (ESRF or ESKF or ESRD or ESKD):ti,ab,kw uremi:ti,ab,kw (#9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17) (#8 AND #18)
MEDLINE	Restless Legs Syndrome/ restless leg$.tw. Ekbom$ syndrome.tw. periodic leg movement$.tw. periodic limb movement$.tw. (PLM or PLMS).tw. (ur?emic polyneuropath$ or ur?emic neuropath$).tw. peripheral polyneuropath$.tw. (nocturnal movement$ or nocturnal leg movement$ or nocturnal limb movement$).tw. or/1‐9 exp Renal Dialysis/ (hemodialysis or haemodialysis or hemodiafiltration or haemodiafiltration or hemofiltration or haemofiltration).tw. dialysis.tw. (PD or CAPD or CCPD or APD).tw. Renal Insufficiency/ exp Renal Insufficiency, Chronic/ Kidney Diseases/ Uremia/ (kidney disease or kidney failure or renal disease or renal failure).tw. (ESRF or ESKF or ESRD or ESKD).tw. (CKF or CKD or CRF or CRD).tw. ur?emi$.tw. or/11‐22 and/10,23
EMBASE	Restless Legs Syndrome/ restless leg$.tw. Ekbom$ syndrome.tw. periodic leg movement$.tw. periodic limb movement$.tw. (PLM or PLMS).tw. (ur?emic polyneuropath$ or ur?emic neuropath$).tw. peripheral polyneuropath$.tw. (nocturnal movement$ or nocturnal leg movement$ or nocturnal limb movement$).tw. or/1‐9 exp Renal Replacement Therapy/ (hemodialysis or haemodialysis or hemodiafiltration or haemodiafiltration or hemofiltration or haemofiltration).tw. dialysis.tw. (PD or CAPD or CCPD or APD).tw. Kidney Disease/ Chronic Kidney Disease/ Kidney Failure/ Chronic Kidney Failure/ Uremia/ (kidney disease or kidney failure or renal disease or renal failure).tw. (CKF or CKD or CRF or CRD).tw. (ESRF or ESKF or ESRD or ESKD).tw. ur?emi$.tw. or/11‐23 and/10,24

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severity	3		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.1 Exercise versus no exercise	2	48	Mean Difference (IV, Random, 95% CI)	‐7.56 [‐14.20, ‐0.93]
1.2 Resistance exercise versus exercise with no resistance	1	24	Mean Difference (IV, Random, 95% CI)	‐11.1 [‐17.11, ‐5.09]
1.3 Resistance exercise versus ropinirole	1	22	Mean Difference (IV, Random, 95% CI)	‐0.55 [‐6.41, 5.31]
2 QOL: physical component score	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
2.1 Resistance exercise versus no exercise	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Resistance exercise versus ropinirole	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3 QOL: mental component summary score	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
3.1 Resistance exercise versus no exercise	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Resistance exercise versus ropinirole	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
4 Quality of sleep: subjective measure	2		Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1 Resistance exercise versus no exercise	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
4.2 Resistance exercise versus exercise with no resistance	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
4.3 Resistance exercise versus ropinirole	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
5 Quality of sleep: Epworth Sleepiness Scale	2		Mean Difference (IV, Random, 95% CI)	Totals not selected
5.1 Resistance exercise versus no exercise	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
5.2 Resistance exercise versus exercise with no resistance	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
5.3 Resistance exercise versus ropinirole	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]

Methods	Study design: parallel placebo‐controlled RCT Study duration: September 2007 to October 2009 Study follow‐up period: 6 months
Participants	Country: Greece Setting: single centre Health status: stable adult HD patients; specialist neurologist diagnosed patients with RLS using IRLSSG criteria Number: 32; treatment group 1 (16); treatment group 2 (8), control group (8) Mean age ± SD (years): treatment group 1 (56.4 ± 12.5); treatment group 2 (55.7 ± 10.4); control group (56.8 ±16.5) Sex (M/F): treatment group 1 (11/4); treatment group 2 (4/3); control group (5/2) Exclusion criteria: diagnosed neuropathies (3, clinically examined by a neurologist); catabolic state (2, opportunistic infections and active inflammation); within 3 months prior to the start of the study CRP > 3.0 mg/L (1); unable to exercise (3); refusal to participate for personal reasons (4)
Interventions	Treatment group 1 Progressive aerobic exercise training (recumbent cycling) at an intensity of 60% to 65% of patient's maximal exercise capacity for 45 minutes during HD session 3 times/wk for a 6 month period Treatment group 2 Ropinirole 0.25 mg in an identical capsule to that of placebo, 2 hours before bed daily for 6 months Control group Placebo (plain flour) in a similar capsule, to be taken 2 hours before bed daily for 6 months. Co‐interventions None
Outcomes	RLS severity using IRLSSG severity rating scale Sleep quality: weekly sleep diary (adapted from University of Massachusetts Medical School) QOL ‐ SF36 Lean body mass Physical performance Depression score using self rated Zung questionnaire
Notes	Funding source: Supported by the National and Community Funds of the Greek Ministry of Development ‐ General Secretariat of Research and Technology and by the European Social Fund
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomised 2:1:1 but no details of how the randomisation was done
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Physical intervention versus drug (double blinded in the placebo versus ropinirole arms)
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Patients aware of the intervention in physical versus drug groups
Incomplete outcome data (attrition bias)   All outcomes	Low risk	One patient withdrew from each group (transplantation (2); chronic infection (1)
Selective reporting (reporting bias)	Low risk	All results of parameters assessed were clearly detailed. However, the reasons for dropouts were not specified; stated only that it was for reasons unrelated to the study
Other bias	Low risk	Government funding

Methods	Study design: single blinded (participant) parallel RCT Study duration: September 2006 to July 2010 Study follow‐up period: 6 months
Participants	Country: Greece Setting: 2 outpatient HD centres Health status: stable adult HD patients with RLS diagnosed by IRLSSG questionnaire; participants on dialysis for ≥ 3 months with adequate dialysis delivery (Kt/V) and with stable clinical condition; none of the recruited patients were engaged in any systematic exercise training program prior to recruitment Number: treatment group (12); control group (12) Mean age ± SD (years): treatment group (59.2 ± 11.8); control group (58.0 ± 10.7) Sex (M/F): treatment group: (9/3); control group (8/4) Exclusion criteria: diagnosed neuropathies; reasons for being in a catabolic state within 3 months prior to the start of the study; unable to exercise
Interventions	Treatment group Progressive aerobic exercise training (pedalling cycle ergometer at 50 revolutions/min) at an intensity of 60% to 65% of patient's maximal exercise capacity for 45 minutes during HD session 3 times/wk for a 6 month period Participated under the supervision of a trained exercise physiotherapist Control group Exercise with no resistance (pedalling cycle ergometer at 50 revolutions/min) for 45 minutes during HD session 3 times/wk for a 6 month period Participated under the supervision of a trained exercise physiotherapist Co‐interventions None of the participants received any medication for RLS prior to the study
Outcomes	Change in IRLS severity score Sleep quality Daily sleepiness Depression score
Notes	Funding source not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised using customised randomisation software
Allocation concealment (selection bias)	Low risk	Used randomisation software
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Even though patients belonging to different groups dialysed on different days, the nature of the intervention (resistance vs exercise with no resistance) would make it easy for the participants to know which arm they have been randomised to
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Patients may have been influenced by the knowledge of their intervention when reporting the outcomes
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No withdrawals in the study
Selective reporting (reporting bias)	Low risk	A number of exercise sessions were reported as incomplete (patients were unable to complete the full 45 min cycling). Reasons for this were stated as personal reasons. Those instances were not systematically recorded and, hence, authors were unable to indicate the level of compliance clearly. The authors gauged compliance as very high
Other bias	Unclear risk	Funding source not reported

Methods	Study design: open‐label crossover RCT Study duration: not reported Study follow‐up period: 10 weeks (4 weeks of first drug, 2 weeks wash out period and 4 weeks of second drug)
Participants	Country: Turkey Setting: outpatient dialysis centre Health status: stable adult HD patients identified as having RLS according to IRLSSG criteria; patients agreed not to take any psychotropic drugs at least 2 weeks before baseline and during the study Number: 15 Mean age ± SD: 45.8 ± 15.3 years Sex (M/F): 10/5 Exclusion criteria: not reported
Interventions	Treatment group Gabapentin 200 mg orally after dialysis (3 times/wk) for 4 weeks Control group Levodopa 125 mg/d, 2 hours before sleep for 4 weeks Co‐interventions None
Outcomes	RLS severity at 0, 4, 10 weeks using a six point severity scale (unclear if the questionnaire is validated or not) QOL (SF‐36) Adverse events reported
Notes	Funding source unclear but no pharmaceutical support Waiting for email reply regarding randomisation and allocation methods Severity scores given in median and range
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Patients and study personnel were aware of the type of intervention
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Only 1 patient excluded (due to medication side effect)
Selective reporting (reporting bias)	High risk	Selectively reported three domains of SF‐36; data not provided to support conclusions reached with regard to sleep parameters
Other bias	Low risk	Funding source: "There was no pharmaceutical industry support of this study"

Methods	Study design: open‐label parallel RCT Study duration: not reported Study follow‐up period: 16 weeks
Participants	Country: Iran Setting: 2 HD centres Health status: stable adult HD patients receiving 3 times/wk with a diagnosis of RLS according to IRLSSG criteria; participants on HD for at least 3 months; sufficient dialysis for at least 3 times/wk; ferritin > 100 ng/mL; TSAT > 20% Number: treatment group (13) control group (13) Mean age ± SD (years): treatment group (32.3 ± 6.7); control group (47.1 ± 13.1) Sex (M/F): 18/8; no split data between the groups provided Exclusion criteria: musculoskeletal disorders causing physical disability; history of ischaemic heart disease (recent myocardial infarction or unstable angina); any catabolic process such as malignancies, opportunistic infections, and infections needing antibiotic therapy during the last 3 months
Interventions	Treatment group Aerobic exercise: pedalling Medi‐Bike continuously for 30 min between 2nd and 3rd hours during dialysis, 3 times/wk for 16 weeks First 5 min after starting, participants had warm‐up time and last 5 min they had cool‐down time Control group No treatment Co‐interventions None
Outcomes	Severity of RLS using RLS questionnaire performed at 0 and 16 weeks QOL questionnaire (SF‐36) performed at 0 and 16 weeks No information on adverse effects
Notes	Funding source not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation method not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No blinding
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Not reported
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Outcome data available
Selective reporting (reporting bias)	Low risk	Outcome in question was reported (severity of RLS)
Other bias	Unclear risk	Funding source not mentioned

Methods	Study design: 4‐arm parallel RCT Study duration: March 2008 to February 2009 Study follow‐up period: 8 weeks
Participants	Country: Iran Setting: HD centre Health status: chronic stable adult HD patients with RLS diagnosed using IRLSSG questionnaire Number: treatment group 1 (15); treatment group 2 (15); treatment group 3 (15); control group (15) Mean age ± SD (years): treatment group 1 (47.4 ± 14.2); treatment group 2 (54.6 ± 15.2); treatment group 3 (49.3 ± 12.9); control group (59.5 ± 17.9) Sex (M/F): treatment group 1 (6/9); treatment group 2 (6/9); treatment group 3 (4/11); control group (9/6) Exclusion criteria: participants receiving medications known to aggravate RLS such as tricyclic antidepressants, selective serotonin reuptake inhibitors, dopamine antagonists, dopamine blocking antiemetics, lithium, and sedative antihistamines; history of kidney stones were excluded due to concerns over increased risk of oxalosis and its joint and vascular complications in HD patients who consume vitamin C
Interventions	Treatment group 1 Vitamin C 200 mg + Vitamin E 400 mg for 8 weeks Treatment group 2 Vitamin C 200 mg + placebo for 8 weeks Treatment group 3 Vitamin E 400 mg + placebo for 8 weeks Control group Placebo for 8 weeks Co‐interventions None
Outcomes	Severity of RLS at 0 and 8 weeks and the change in the score using IRLSG scoring system (0 to 40 max) Adverse events
Notes	Funding source: grant from the Shiraz University of Medical Sciences, Shiraz, Iran
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Blocked randomisation with a fixed block size of four by randomisation sequence generator
Allocation concealment (selection bias)	Low risk	1:1:1:1 random assignment to the 4 groups; this was done by an investigator who had no clinical involvement in the study
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double blind
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Double blind
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Used random sequence generating software
Selective reporting (reporting bias)	Low risk	Clear reporting of side effects. Study protocol clear enough from the methods section
Other bias	Low risk	Funded by a Grant from the Shiraz University of Medical Sciences, Shiraz, Iran

Methods	Study design: parallel RCT Study duration: not reported Study follow‐up period: 4 weeks
Participants	Country: USA Setting: dialysis centre in Rochester, USA Health status: stable adult HD and PD (3 in placebo group) diagnosed with RLS; concurrent medications used to treat RLS were not discontinued or tapered, but new medications, including oral iron, could not be added within 1 month before entry into this study and the dosage of medications used to treat RLS could not be changed within this period or during the study Number: treatment group (11); control group (14) Mean age ± SD (years): treatment group (55.8 ± 11); control group (54.3 ± 3.7) Sex (M/F): treatment group (6/5); control group (10/4) Exclusion criteria: childbearing potential; severe liver disease; polycythaemia or evidence for haemochromatosis; a history of 10 or more blood transfusions during the 2 years before the study; history of hypersensitivity to IV iron; receipt of any IV iron within 1 month of enrolment; weight < 50 kg; URR < 65% (unless kinetic modelling using Kt/V was > 1.2); a change in dialysis prescription within 3 months of entry; fistula recirculation > 12%; active inflammatory or rheumatologic disease
Interventions	Treatment group IV iron dextran 1000 mg IV diluted in 500 mL on dialysis (administered only once during the study period) Control group 500 mL of normal saline infused during dialysis (administered only once during the study period) Both placebo and drug were infused during dialysis by infusion pump with the medication (or placebo) and tubing covered with an opaque obscuring sleeve so that neither the patient,  investigator, nor study nurse could detect which was being administered
Outcomes	RLS severity assessed by a non‐validated questionnaire at 0, 1, 2, 4 weeks (scores range from 0 to 10) Multiple other lab parameters such as haemoglobin, iron stores were measured Adverse events
Notes	Funding source not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No clear mention of the randomisation process
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Both placebo and drug were infused during dialysis by infusion pump with the medication (or placebo) and tubing covered with an opaque obscuring sleeve so that neither the patient, investigator, nor study nurse could detect which was being administered
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Patients were blinded to the treatment
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Outcome data available
Selective reporting (reporting bias)	Low risk	Protocol not available but published report contained expected outcome (Improvement in RLS severity) Side effects were also reported
Other bias	Unclear risk	Funding source not reported

Methods	Study design: double blind crossover RCT Study duration: not reported Study follow‐up period: 13 weeks (6 weeks of treatment with first agent, 1 week washout period and 6 weeks of treatment with second agent)
Participants	Country: USA Setting: HD centre in Portland Veterans Affairs Medical centre, Portland, USA Health status: stable chronic adult HD patients with RLS diagnosed according to criteria similar to the current IRLSSG criteria Number: 16 Mean age ± SD: 64.1 ± 5.9 years Sex (M/F): 15/1 Exclusion criteria: participants with other cause of leg discomfort on neurological examination
Interventions	Treatment group Gabapentin 300 mg orally at the end of dialysis (3 times/wk) for 6 weeks Control group Placebo similar to gabapentin administered orally at the end of dialysis (3 times/wk) for 6 weeks Treatment administered under the direct supervision on nurse at the end of dialysis treatment. One week washout period between 2 treatments
Outcomes	RLS severity assessed by non‐validated Questionnaire at 0, 6, 13 weeks
Notes	Funding source: Drug was supplied by Pharmaceutical company
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No clear mention how randomised
Allocation concealment (selection bias)	Unclear risk	Method of concealment not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Patients, nurses, and physicians were blinded to treatment assignment
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Assessments (questionnaires) were carried out while subjects and staff were still blinded to treatment
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Clearly mention drop outs and withdrawals with specified reasons
Selective reporting (reporting bias)	Unclear risk	No study protocol but expected outcome (improvement in severity of RLS) is clearly discussed
Other bias	High risk	"Gabapentin was supplied by Parke‐Davis Pharmaceuticals"

Methods	Study design: crossover RCT Study duration: not reported Study follow‐up period: 8 weeks (unclear if there was a washout period)
Participants	Country: Germany Setting: Department of Neurology in the Klinikum Grosshadern Health status: participants both with idiopathic RLS and with uraemic RLS were included (criteria for RLS similar to IRLSSG criteria); more than 5 PLM related ‐arousals/h of sleep; sleep latency of more than 25 min; sleep efficiency index < 85% in addition to symptoms of RLS Number: 11 (patients with uraemic RLS out of a total of 32 patients in the study) Mean age ± SD: 49 ± 11 years Sex (M/F): 6/5 Exclusion criteria: patients with signs of any other sleep disorder on polysomnography, especially narcolepsy and sleep apnoea syndrome; receiving neuroleptic or antidepressant medications; any severe additional illness or history of drug abuse; pregnant or lactating women and women without safe contraceptive methods
Interventions	Treatment group Madopar (L‐dopa 100 mg + benserazide 25 mg) given orally 1 hour before bedtime for 4 weeks; dose could be doubled after 2 weeks Control group Placebo given orally 1 hour before bedtime for 4 weeks Co‐interventions None
Outcomes	Polysomnographic studies Actigraphy Subjective rating (using modified 50‐mm Hamburger VAS) Physician's rating (CGI) Safety evaluation for rate of side effects of medications
Notes	Funding source not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information on the randomisation procedure
Allocation concealment (selection bias)	Low risk	Double blind
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double blind
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	No clear statement of blinding of outcome assessment, but assessments of outcome (polysomnographic studies, Actigraphy, subjective rating and physician's rating) were carried out at different points of the study while participants and investigators were still blinded
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Data regarding different assessment methods were clearly shown and data regarding both groups (idiopathic versus uraemic RLS) were clearly shown
Selective reporting (reporting bias)	Low risk	No protocol but outcomes (improvement in RLS) assessment clearly outlined
Other bias	Unclear risk	Funding source not reported

Study	Reason for exclusion
Ausserwinkler 1989	Wrong population: participants with uraemic polyneuropathy which is a sensorimotor polyneuropathy caused by uraemic toxins
Facchini 2004	Wrong population: participants with uraemic polyneuropathy which is a sensorimotor polyneuropathy caused by uraemic toxins
FINESSE Study 2010	Wrong population: participants with uraemic polyneuropathy which is a sensorimotor polyneuropathy caused by uraemic toxins
Kramer 1988	It was a study of uraemic neuropathy, which is a sensorimotor polyneuropathy caused by uraemic toxins and it can be a cause for secondary RLS which is one of our exclusion criteria
N0203077917	No data has been published since the study was first registered in the UK in 2002
Okada 2000	It was a study of uraemic neuropathy, which is a sensorimotor polyneuropathy caused by uraemic toxins and it can be a cause for secondary RLS which is one of our exclusion criteria
Pieta 1998	It was a study of periodic limb movement disorder and not RLS, so excluded
Sprenger 1983	Wrong population: participants with uraemic polyneuropathy which is a sensorimotor polyneuropathy caused by uraemic toxins
Walker 1996	The primary outcome was measured objectively using polysomnography and there were no data on subjective improvement

Methods	Parallel RCT Subjects completing the screening period will be randomised (1:1) to receive ropinirole immediate release (IR) or placebo for 12 weeks.
Participants	Male and female patients aged 18 to 79 years Inclusion criteria at week ‐1 (at the screening visit): patients who are diagnosed with symptomatic restless legs syndrome associated with CKD managed with haemodialysis. RLS are diagnosed based on the IRLSSG diagnostic criteria.QTc criteria. Patients with QTc < 450 msec or < 480 msec for patients with bundle branch block Exclusion criteria at week ‐1 (at the screening visit): signs of primary RLS; sleep disorder not associated with RLS (narcolepsy, sleep terror disorder, sleepwalking disorder, breathing related sleep disorder; complication of movement disorder; severe hepatic/cardiac/pulmonary disorder or haematopoietic disorder other than those on haemodialysis (including haemofiltration and haemodiafiltration); history of malignancies within the past 5 years, with the exception of basal cell carcinoma or carcinoma in situ of cervix; medical history or complication of substance abuse; supine systolic blood pressure(SBP) < 100 mm Hg or >190 mm Hg or supine diastolic blood pressure (DBP) ≥ 120 mm Hg before the dialysis; intolerant to ropinirole hydrochloride (HCl) or other dopamine agonists or ropinirole HCl or other dopamine agonists are considered to be of safety concern by the investigator/sub‐investigator; history of augmentation or end‐of‐dose‐rebound in the early morning after medications of dopamine agonists (including ropinirole HCl) and/or L‐dopa; without night time sleeping habit (e.g. night‐shift worker) and those who must drastically change the habitual bedtime during the study duration; participated in another clinical study of an investigational product or medical device within the last 12 weeks prior to the start of the screening period; pregnant or lactating, who may be pregnant, or who plan for pregnancy during the study; current or chronic history of liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones); presence of HBsAG, positive hepatitis C test result within 3 months of screening; medical conditions which could affect efficacy and safety assessment; unable to discontinue prohibited medications during the screening period; will imminently receive a transplant; changed the dose or administration method of anxiolytics or hypnotics and sedatives within the last 4 weeks prior to the start of the screening period, and/or patients who used more than two drugs; others whom the investigator/sub‐investigator considers ineligible for the study. Exclusion criteria at week 0 (start of the treatment period): supine SBP of < 100 mm Hg or > 190 mm Hg or supine DBP of ≥120 mm Hg before the dialysis at Week 0; started treatment with medications including an oestrogen drug product, anxiolytics, hypnotics and sedatives or who have changed the dose or administration method of such medications between week ‐1 (start of the screening period) and week 0 (start of the treatment period); serum ferritin level is < 10 μg/L (ng/mL) at the screening visit
Interventions	Treatment group The treatment with IR will be started at the initial dose of 0.25 mg/d within 1 to 3 hours before bedtime. The maximum available dose is 3 mg/d. For all subjects completing short‐term period and entering the long‐term treatment period, the open‐label treatment will be started from IR 0.25 mg/d regardless of dose levels during short‐term period. The dose will be upward titrated from 0.25 mg/d to 0.5 mg/d and after that in increments of 0.5 mg/d until sufficient efficacy is obtained (targeting "much improved" or "very much improved" in the CGI‐Improvement scores without safety/tolerability problem Control group Matching placebo to IR in the double‐blind treatment period. All participants completing the double‐blind treatment period were eligible to continue in the open‐label long‐term treatment period. In the open‐label period, participants received ropinirole IR tablets in the same way as in the ropinirole IR‐ropinirole IR group.
Outcomes	IRLS rating scale at week 0 and week 12 Number with the indicated CGI‐improvement scores at week 12 RLS‐QOL PSQI Mean daily number of hours of RLS symptoms Drug clearance rate on‐dialysis and off‐dialysis
Notes	This study was prematurely terminated after 5 months had passed since its initiation, because GlaxoSmithKline concluded that it was impossible to recruit sufficient participants within a reasonable timeframe. In this study, no participants had completed. The maximum duration was 24 weeks plus follow‐up (up to week 64) Some data available on ClinicalTrials.gov

Methods	Study design: parallel multicentre RCT
Participants	Male and female patients aged 18 to 85 years Inclusion criteria: ESKD requiring haemodialysis. Diagnosis of RLS based on the 4 cardinal diagnostic clinical features according to the IRLSSG. Initial response to previous dopaminergic treatment for RLS, or has had no previous dopaminergic treatment (ie, de novo). Score of ≥ 15 points on the IRLS (indicating moderate to severe RLS) at baseline score of ≥ 11 points on the RLS‐Diagnostic Index at baseline score of ≥ 4 points on the CGI Item 1 assessment (indicating moderately ill) at baseline. Scores ≥ 15 PLM/h on the PLMI based on polysomnography (recorded during the second night) as assessed by the investigator at Baseline. Exclusion criteria: clinically relevant polyneuropathy or varicosis which cannot be clearly differentiated from RLS symptoms in the opinion of the investigator; clinically relevant concomitant diseases; other central nervous system diseases; evidence of an impulse control disorder according to the modified Minnesota Impulsive Disorders Interview; lifetime history of suicide attempt, or has suicidal ideation in the past 6 months; prior history of psychotic episodes; history of symptomatic (not asymptomatic) orthostatic hypotension; clinically relevant CVD; clinically relevant venous or arterial peripheral vascular disease malignant neoplastic disease requiring therapy within 12 months of visit 1; treatment with any of the following drug classes: neuroleptics, norepinephrine and dopamine reuptake inhibitors, gabapentin, budipine, dopamine antagonist antiemetics (except domperidone), opioids, monoamine oxidase (MAO) inhibitors, catechol‑O‑methyltransferase inhibitors, or psychostimulants; pregnancy, nursing, childbearing potential who is not surgically sterile, 2 years postmenopausal, or does not use 2 combined effective methods of contraception; previous treatment with dopamine agonists within a period of 14 days prior to baseline, or L‐dopa within 7 days prior to baseline; medical history indicating intolerability to dopaminergic therapy (if pretreated) or has experienced augmentation when previously treated with any dopaminergic agent; subject has received previous treatment with rotigotine; known hypersensitivity to any of the components of the study medication, such as a history of significant skin hypersensitivity to adhesives, known hypersensitivity to other transdermal medications, or unresolved contact dermatitis
Interventions	Treatment group Rotigotine: transdermal patch, 1 mg/24 h, 2 mg/24 h or 3 mg/24 h once daily depending on optimal dose; maximal dose is 3 mg/24 h Control group Placebo: transdermal patch; patches matching to active treatment patches in size and appearance
Outcomes	Ratio from baseline in PLMI Change from baseline PLMI IRLSSG CGI RLS‐6 (rating scales 1 to 6) PLMSAI Sleep efficiency RLS‐QOL SF‐36 mental component summary SF‐36 physical component summary
Notes	The recruitment for the SP0934 study began in April 2012. It concluded in October 2013. This was a multicentre study with subjects enrolled by 9 sites across Europe and 6 sites across the United States. Some data available on ClinicalTrials.gov

Methods	Study design: parallel RCT
Participants	Inclusion criteria: adults and children with ESKD requiring HD or PD for a duration of at least 3 months Exclusion criteria: history of consumption > 300 µg/d of biotin; oral contraceptive therapy containing high amounts of oestrogen; women of childbearing age
Interventions	Treatment group Biotin: 10,000 µg biotin daily for 8 weeks Control group Placebo: sugar pill
Outcomes	Biotin status Change in RLS symptoms
Notes	ClinicalTrials.gov last updated: 12 December 2013 No data available

Methods	Study design: crossover RCT
Participants	Aged > 15 years
Interventions	Treatment group 1 Capsules of gabapentin 200 mg after every HD for 4 weeks, 2 hours before sleep Treatment group 2 Tablet of levodopa‐C 110 mg nightly 2 hours before sleep for 4 weeks
Outcomes	Severity of RLS Severity of sleep disorder QOL Day time sleepiness Drug adverse reaction
Notes	Some study data no longer accessible (figures and tables)

PERMALINK

Interventions for chronic kidney disease‐associated restless legs syndrome

Seerapani Gopaluni

Mohamed Sherif

Naim A Ahmadouk

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Inclusion criteria

Exclusion criteria

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

1.

Included studies

Design

Sample sizes

Setting

Participants

Interventions

Outcomes

1. Adverse events.

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Exercise interventions

Severity of restless legs syndrome

1.1. Analysis.

Quality of Life

1.2. Analysis.

1.3. Analysis.

Quality of sleep

1.4. Analysis.

1.5. Analysis.

Adverse events

Pharmacological interventions

Severity of restless legs syndrome

Gabapentin versus placebo

2.1. Analysis.