Ropinirole is effective in the long-term management of restless legs syndrome: a randomized controlled trial.

The objective of this study was to investigate the long-term efficacy of ropinirole in patients with restless legs syndrome (RLS) and to assess the potential for relapse after the discontinuation of active treatment. Patients with primary RLS (n = 202) received single-blind ropinirole for 24 weeks. Patients meeting treatment continuation criteria were randomized to double-blind treatment with ropinirole or placebo for a further 12 weeks. The primary efficacy variable was the proportion of patients relapsing during double-blind treatment. Additional efficacy measures included time to relapse, withdrawals due to lack of efficacy, improvement on the Clinical Global Impression-Improvement (CGI-I) scale, change in International Restless Legs Scale (IRLS) score during double-blind treatment, and changes in sleep and quality of life (QoL) parameters. Significantly fewer patients relapsed on ropinirole than on placebo (32.6% vs. 57.8%; P = 0.0156). Time to relapse was longer with ropinirole and more patients withdrew due to lack of efficacy with placebo. Patients showed improvements in IRLS and CGI-I scores, sleep and QoL parameters with single-blind ropinirole, which were better maintained when ropinirole was continued during the double-blind phase, but reduced with placebo. Ropinirole was well tolerated; adverse events were typical for dopamine agonists. Ropinirole was highly effective and well tolerated in the long-term management of RLS, with pharmacological effect over 36 weeks.     

Clinical efficacy of ropinirole for restless legs syndrome is not affected by age at symptom onset

ObjectiveTo determine whether clinical response to the dopamine agonist, ropinirole, in the treatment of primary restless legs syndrome (RLS), depends upon the age-at-onset of RLS symptoms.MethodsPooled data from four 12-week, randomized, double-blind, placebo-controlled studies of ropinirole in patients with moderate-to-severe primary RLS were analyzed post hoc. The relationship between age-at-onset and response to treatment, based on change from the baseline International Restless Legs Syndrome Study Group (IRLSSG) rating scale (the International Restless Legs Scale [IRLS]) total score and the proportion of responders (rated ‘much’/‘very much’ improved) on the Clinical Global Impression–Improvement (CGI-I) scale, was explored.ResultsThe range of age-at-onset of RLS symptoms was 2–75 years. No relationship was observed between the age-at-onset of RLS symptoms and baseline IRLS total score (correlation r = −0.06), and between dose administered at Week 12 last observation carried forward (LOCF) and age-at-onset (r = −0.04). The age-at-onset by treatment interaction was non-significant (P = 0.952 for the IRLS and P = 0.716 for the CGI-I scale), indicating there was no significant relationship between age-at-onset and the magnitude of ropinirole treatment effect.ConclusionsThese data suggest that ropinirole provides effective relief of symptoms, regardless of age at RLS symptom onset.     

The reliability, validity and responsiveness of the International Restless Legs Syndrome Study Group rating scale and subscales in a clinical-trial setting

PATIENTS AND METHODS: To assess the reliability, validity, and responsiveness of the International Restless Legs Syndrome Study Group's rating scale (the International Restless Legs Scale (IRLS)) (V2.0), using pooled data from two matching, placebo-controlled studies of ropinirole for treating Restless Legs Syndrome (RLS). RESULTS: Pooled patient samples comprised 550 patients in the baseline (validation) sample and 439 patients in the week 12 longitudinal (responsiveness) sample. Factor analysis revealed acceptability of the IRLS total score (accounting for 40% of the variance) and that nine of the 10 IRLS items could also be assigned to two distinct subscales, the symptoms or symptoms impact subscales. The IRLS total score, symptoms and symptoms impact subscales had acceptable construct validity, internal consistency reliability (alpha=0.81, 0.80, and 0.76, respectively), and concurrent validity (r=-0.68, -0.52, -0.70, respectively, with the Restless Legs Syndrome Quality of Life questionnaire (RLSQoL) overall life impact score). IRLS scores differed significantly between different levels of sleep problems and Clinical Global Impression (CGI) of health status (P<0.0001), indicating known groups and clinical validity, respectively. Changes in scores differed significantly among CGI 'global improvement' levels (P<0.0001), providing evidence of responsiveness. CONCLUSIONS: The IRLS total score, symptoms, and symptoms impact subscales are reliable, valid, and responsive in a clinical trial setting.     

Ropinirole in the treatment of restless legs syndrome: results from the TREAT RLS 1 study, a 12 week, randomised, placebo controlled study in 10 European countries

OBJECTIVE: To assess the efficacy, safety, and tolerability of ropinirole in the treatment of patients with restless legs syndrome. METHODS: A 12 week, prospective, double blind, randomised comparison involving 284 patients from 10 European countries. All participants had a score of > or =15 on the international restless legs scale (IRLS). Patients were randomised (1:1) to receive either ropinirole 0.25-4.0 mg once daily or placebo. The primary efficacy end point was mean change from baseline to week 12 in total IRLS score. Global improvements (clinical global impression (CGI) scale) and improvements in sleep, health related quality of life (QoL; using generic and disease specific measures), work, and other activities were also assessed. RESULTS: 112/146 patients (76.7%) taking ropinirole and 109/138 (79.0%) taking placebo completed the study. Improvement in IRLS at week 12 with ropinirole (mean (SD) dose, 1.90 (1.13) mg/day) was greater than with placebo (mean (SE): -11.04 (0.719) v -8.03 (0.738) points; adjusted difference = -3.01 (95% confidence interval (CI), -5.03 to -0.99); p = 0.0036). More patients in the ropinirole group (53.4%) showed improvement on the CGI scale at week 12 than in the placebo group (40.9%; adjusted odds ratio = 1.7 (1.02 to 2.69); p = 0.0416). Significant differences on both IRLS and CGI scales favouring ropinirole were apparent by week 1. Ropinirole was also associated with significantly greater improvements in sleep and QoL end points. The most common adverse events were nausea and headache. CONCLUSIONS: Ropinirole improves restless legs syndrome compared with placebo, with benefits apparent by week 1. It is generally well tolerated.     

A 52-week open-label study of the long-term safety of ropinirole in patients with restless legs syndrome

OBJECTIVE: To assess the long-term safety and efficacy of ropinirole in the treatment of patients with restless legs syndrome (RLS) over 52 weeks. METHODS: A 52-week, multicentre, open-label continuation study involving 310 patients, conducted in 11 countries. Eligible patients from four parent studies were invited to participate. At parent study entry, all patients had a score of > or =15 on the International Restless Legs Scale (IRLS). In this continuation study, all participants received ropinirole, 0.25-4.0 mg once daily, for 52 weeks. The primary study objective was to evaluate the safety of ropinirole. Efficacy was assessed by change in IRLS score, as well as by global improvements (clinical global impression [CGI] scale) and improvements in measures of sleep, work productivity, and quality of life. RESULTS: Overall, 251 (81.0%) patients completed the study. The mean ropinirole dose at study end was 1.90 mg/day. A total of 282 patients (91.3%) reported > or = 1 adverse event. For the majority of patients, the reported adverse events were mild or moderate in intensity. The most common adverse event was nausea. Adverse events led to discontinuation in 8.7% of patients. At week 52, IRLS scores improved by an average of 12.0 points from baseline, and 82.8% of patients were 'much improved' or 'very much improved' on the CGI-improvement scale. Ropinirole treatment was also associated with improvements in measures of sleep and quality of life. CONCLUSIONS: Ropinirole was well tolerated and therapeutic efficacy was maintained over 52 weeks in patients with RLS.     

Efficacy of gabapentin enacarbil in adult patients with severe primary restless legs syndrome

AimAssess efficacy and tolerability of gabapentin enacarbil (GEn) in adults with severe primary restless legs syndrome (RLS).MethodsWe pooled data from three 12-week, double-blind, placebo-controlled, randomized trials (NCT00298623, NCT00365352, NCT01332305) across GEn 600-mg, GEn 1200-mg, and placebo treatment groups for severe primary RLS (baseline International Restless Legs Scale (IRLS) total score ≥24). Co-primary end points at week 12 were mean change from baseline in IRLS total score and proportion of responders (“much”/very much” improved) on the investigator-rated Clinical Global Impression – Improvement (CGI-I) Scale. Outcomes for individual IRLS items (eg, sleep, mood, quality of life, pain, safety) were assessed.ResultsA total of 309 patients had severe primary RLS (placebo, n = 110; GEn 600 mg, n = 80; GEn 1200 mg, n = 119). GEn 600 mg and 1200 mg significantly improved least-squares mean IRLS total scores versus placebo at week 12 (placebo, −12.3; GEn 600 mg, −16.3; GEn 1200 mg, −18.0; treatment difference vs. placebo, both p <0.01). Significantly more patients with severe primary RLS treated with GEn 600 mg (64%) and 1200 mg (74%) were CGI-I responders at week 12 versus placebo (42%; p <0.01 for both GEn doses). Both GEn doses led to significant improvements in the other outcomes explored versus placebo at week 12. The most frequent treatment-emergent adverse events (TEAEs) were somnolence (GEn, 21–24%; placebo, 3%) and dizziness (GEn, 14–19%; placebo, 3%).ConclusionsGEn (600 mg or 1200 mg) once daily significantly improved RLS symptoms and consequences of these symptoms in severe primary RLS. The most frequent TEAEs were somnolence and dizziness.     

Ropinirole as a treatment of restless legs syndrome in patients on chronic hemodialysis: an open randomized crossover trial versus levodopa sustained release

OBJECTIVE: Restless legs syndrome (RLS) is a common neurologic condition characterized by uncomfortable and unpleasant sensations in the legs, occurring primarily at rest, which are usually worse in the evening and are alleviated by movement. RLS is present in 20-40% of patients with renal failure. This study was a 14-week open, randomized, crossover trial of ropinirole vs. levodopa sustained release (SR) in 11 patients with RLS on chronic hemodialysis. METHODS: Eleven patients (7 men, 4 women) were enrolled in the study. They received either levodopa SR or ropinirole for 6 weeks, followed by a washout week, then the alternate treatment for 6 weeks. Patients rated the severity of RLS by means of a 6-item questionnaire developed by the International Restless Legs Study Group (6-item IRLS), by the Clinical Global Impression (CGI) scale, and by sleep diaries. RESULTS: Under treatment with levodopa SR, 1 patient presented severe vomiting, leading to study discontinuation. The 10 patients who completed the study reported a 33.5% improvement (from 16.7 +/- 3.2 to 11.1 +/- 4; P < 0.001) of the 6-item IRLS scores during levodopa SR treatment and a 73.5% improvement (from 16.6 +/- 2.8 to 4.4 +/- 3.8; P < 0.001) during ropinirole treatment. By the end of the study the mean levodopa SR dosage was 190 mg/d and the mean ropinirole dosage was 1.45 mg/d. Ropinirole was superior to levodopa SR in reducing 6-item IRLS scores (P < 0.001) and in increasing sleep time (P < 0.001). The patient CGI scale showed a significant difference favoring ropinirole (P < 0.01). There was no significant carryover or period effect for any outcome measure. Four patients reported a complete reversion of RLS symptoms during ropinirole treatment at doses ranging from 0.25-2 mg/d. CONCLUSIONS: These results suggest that ropinirole is more effective than levodopa SR in the treatment of RLS in patients on chronic hemodialysis.     

Predictors of clinical response in a double-blind placebo controlled crossover trial of gabapentin enacarbil for restless legs syndrome

ObjectivesRestless Legs Syndrome (RLS) is a sensory-motor disorder which produces sleep disturbance. Using data from a large clinical trial of gabapentin enacarbil (GEn) we sought to assess the ability of baseline, and changes from baseline, in clinical trial endpoints to predict treatment response.MethodsData were derived from a randomized, double-blind, placebo-controlled, crossover polysomnography study of gabapentin enacarbil 1200 mg (n = 121) or placebo (n = 123). Efficacy evaluations included: sleep measures from polysomnography, subjective sleep measures, Suggested Immobilization Test (SIT) measures, and International Restless Legs Severity Scale (IRLS) and Clinical Global Impression-Improvement (CGI-I). Correlations were evaluated using Spearman's rank correlation coefficients. Predictors of treatment response were separately assessed for GEn and placebo using categorical IRLS and CGI-I outcomes. Stepwise logistic regression models ascertained which combination of baseline and change from baseline variables predicted response.ResultsModerate to large correlations were observed between changes in the IRLS and changes in subjective sleep for both GEn and placebo, substantially larger for GEn than placebo. Small to moderate correlations were present between the change in IRLS and the change in SIT-discomfort for both GEn and placebo. In the stepwise regression, for both GEn and placebo, baseline and change from baseline SIT discomfort, as well as change in sleep quality, were strong predictors of response.ConclusionsChanges in sleep quality, and baseline and changes in SIT discomfort were prominent predictors of treatment response for GEn and placebo. Predictors of treatment response may allow for more targeted enrollment in future clinical trials and may provide insights into the efficacy of RLS treatments.     

Meta-analysis of the efficacy and tolerability of pramipexole versus ropinirole in the treatment of restless legs syndrome

OBJECTIVE: In the absence of comparative trials a meta-analysis was performed to compare the efficacy and tolerability of the non-ergot derived dopamine agonists, pramipexole and ropinirole, in restless legs syndrome (RLS). METHODS: Frequentist fixed and random-effects models were pre-specified for the direct comparisons and a Bayesian approach for the indirect comparison. Efficacy outcomes included the mean change from baseline in the International RLS Study Group Rating Scale (IRLS) score and the percentage of responders on the clinical global impressions - improvement scale (CGI-I). Safety outcomes included the incidence of withdrawal and adverse events. RESULTS: The direct meta-analysis confirmed superior efficacy for both treatments versus placebo for the IRLS (pramipexole: -5.45; 95% CI: -7.70; -3.20; ropinirole: -3.16; 95% CI: -4.26; -2.05) and the CGI-I (pramipexole: OR=2.98; 95% CI: 2.08; 4.26; ropinirole: OR=1.99; 95% CI: 1.52; 2.60). Placebo comparisons showed a significantly higher incidence of nausea for pramipexole (p<0.01), whereas nausea, vomiting, dizziness, and somnolence were significantly higher for ropinirole (all p<0.01). The indirect comparison showed with a probability of > or = 95%, a superior reduction in the mean IRLS score (-2.33; 95% credibility interval [CrI]: -4.23; -0.41), higher CGI-I response rate (OR=1.50; 95% CrI: 0.97; 2.32) and significantly lower incidence of nausea, vomiting, and dizziness for pramipexole compared to ropinirole. CONCLUSION: Differences in efficacy and tolerability favouring pramipexole over ropinirole can be observed. These findings should be further confirmed in head-to-head clinical trials.     

A randomized,double-blind, 6-week,dose-ranging study of pregabalin in patients with restless legs syndrome

ObjectiveThis study evaluated the dose-related efficacy and safety of pregabalin in patients with idiopathic restless legs syndrome (RLS).MethodsThis six-arm, double-blind, placebo-controlled, dose–response study randomized patients (N = 137) with moderate-to-severe idiopathic RLS in an equal ratio to placebo or pregabalin 50, 100, 150, 300, or 450 mg/day. The dose–response was characterized using an exponential decay model, which estimates the maximal effect (E_max) for the primary endpoint, the change in the International Restless Legs Study Group Rating Scale (IRLS) total score from baseline to week 6 of treatment. Secondary outcomes included Clinical Global Impressions-Improvement Scale (CGI-I) responders, sleep assessments, and safety.ResultsThe separation of treatment effect between placebo and pregabalin began to emerge starting at week 1 which continued and increased through week 6 for all dose groups. The IRLS total score for pregabalin was dose dependent and well characterized for change from baseline at week 6. The model estimated 50% (ED₅₀) and 90% (ED₉₀) of the maximal effect in reducing RLS symptoms that occurred at pregabalin doses of 37.3 and 123.9 mg/day, respectively. A higher proportion of CGI-I responders was observed at the two highest doses of pregabalin (300 and 450 mg/day) versus placebo. Dizziness and somnolence were the most common adverse events and appeared to be dose-related.ConclusionsIn this 6-week phase 2b study, pregabalin reduced RLS symptoms in patients with moderate-to-severe idiopathic RLS. The symptom reduction at week 6 was dose-dependent with 123.9 mg/day providing 90% efficacy. Pregabalin was safe and well tolerated across the entire dosing range.     

Randomized, double-blind, placebo-controlled, short-term trial of ropinirole in restless legs syndrome

BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) is a condition characterized by an urge to move the legs, usually accompanied by lower limb paresthesias. These symptoms worsen at rest, are relieved by activity, and are worse at night. Previous studies have suggested that dopaminergic drugs such as L-dopa and dopamine agonists, as well as benzodiazepines and opioids, can treat RLS successfully. The purpose of this study was to test the clinical efficacy of ropinirole, a D2/D3 agonist, in the treatment of RLS in a double-blind, short-term, placebo-controlled clinical trial. PATIENTS AND METHODS: After undergoing successful open-label titration and dose adjustments with ropinirole for RLS symptoms over a period of 4 weeks, 22 RLS patients (mean age=50.8; mean duration of symptoms=26.1 years) were randomized to receive either placebo (n=13) or ropinirole (n=9) for 2 additional weeks. Outcome measures included assessment of periodic leg movements in sleep (PLMS) recorded with nocturnal polysomnography and RLS symptoms as assessed with the International Restless Legs Syndrome Study Group (IRLSSG) Rating Scale. Secondary outcomes included sleep macroarchitecture. RESULTS: Results indicated that relative to placebo, ropinirole, at a mean dose of 1.4mg HS significantly decreased PLMS and RLS symptoms. Sleep macroarchitecture did not change. Side effects were typical of all dopamine agonists and were dose related. The majority of patients elected to continue treatment with ropinirole upon study completion. CONCLUSIONS: Ropinirole successfully treated long-standing RLS and can be considered a viable short-term treatment for this condition.     

Open-label study of the long-term efficacy and safety of pramipexole in patients with Restless Legs Syndrome (extension of the PRELUDE study)

BACKGROUND AND OBJECTIVE: To demonstrate the long-term efficacy and safety of pramipexole for Restless Legs Syndrome (RLS) using physician and patient RLS ratings, along with subjective assays of sleep parameters, in a 26-week, open-label trial. PATIENTS AND METHODS: Among 107 Finnish adults with moderate to severe RLS, pramipexole initiated at 0.125 mg/day was titrated to a maximum 0.75 mg/day. Efficacy evaluations included the International RLS Study Group Rating Scale (IRLS), Patient Global Impression (PGI) scale, Clinical Global Impressions-Improvement (CGI-I) scale, Epworth Sleepiness Scale (ESS), and Short Form-36 (SF-36) Health Survey. Subjective Sleep Quality was assessed by patient ratings of sleep and morning tiredness. Safety was documented by Adverse Events reported in >5% of patients. RESULTS: The mean reduction in IRLS score was 73.5% (P<0.05). The IRLS responder rate, defined by score reduction of >or= 50%, was 81.3%. On the PGI scale, 89.7% of patients rated themselves as "very much" or "much" better. By CGI-I assessment, 94.8% of patients were considered either "very much" or "much" improved. Mean ESS score showed a modest but statistically significant reduction (P<0.05) within the normal range, indicating that long-term pramipexole did not increase daytime sleepiness. On the SF-36 all 8 domains showed improvement, 5 of them statistically significant (P<0.05) and 4 of these 5 (role-physical, bodily pain, vitality, and role-emotional) by >10 points on a 100-point scale. Subjective Sleep Quality also improved. The most frequent Adverse Events were influenza (17.8%), headache (15.0%), and fatigue (10.3%). CONCLUSION: Pramipexole is well tolerated and effective for long-term treatment of RLS.     

Efficacy of pramipexole in restless legs syndrome: a six-week, multicenter, randomized, double-blind study (effect-RLS study).

We evaluated the efficacy of pramipexole versus placebo in restless legs syndrome (RLS) for 6 weeks. Overall, 345 patients were randomly assigned in a 1:2 ratio to receive either placebo (n = 115) or pramipexole (n = 230) with a starting dose of 0.125 mg/day. The dose was individually optimized according to the Patient Global Impression (PGI) assessment, up to a maximum of 0.75 mg/day. The primary endpoint consisted of two assessments: the change from baseline in the International RLS Study Group Rating Scale (IRLS) and the proportion of patients with Clinical Global Impressions-Improvement (CGI-I) assessments of "much/very much improved" (CGI-I responders) at week 6. Secondary endpoints included PGI and IRLS responder rates. Patient demographics and baseline characteristics were comparable between treatment groups. At baseline, mean IRLS scores were 24.9 (placebo) and 24.7 (pramipexole), representing severely affected patients. After 6 weeks, adjusted mean reductions (+/-SE) in IRLS score were 5.7 (+/-0.9) for placebo (median dose 0.47 mg/day) and 12.3 (+/-0.6) for pramipexole (median dose 0.35 mg/day; P < 0.0001). CGI-I responder rates were 32.5% (placebo) and 62.9% (pramipexole) (P < 0.0001). For all secondary endpoints, pramipexole showed superior results. Pramipexole was well tolerated throughout the study.     

Relation of the International Restless Legs Syndrome Study Group rating scale with the Clinical Global Impression severity scale,the restless legs syndrome 6-item questionnaire,and the restless legs syndrome-quality of life questionnaire

BackgroundThe SP790 study (ClinicalTrials.gov, NCT00136045) showed benefits of rotigotine over placebo in improving symptom severity of restless legs syndrome (RLS), also known as Willis-Ekbom disease, on the International Restless Legs Syndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 (CGI-1), RLS 6-item questionnaire (RLS-6), and the RLS-quality of life questionnaire (RLS-QoL) in patients with moderate to severe idiopathic RLS. To provide clinical context for the IRLS and to guide the choice of assessment scales for RLS studies, our post hoc analysis of SP790 data evaluated associations between the IRLS and the CGI-1, IRLS and RLS-6, and the IRLS and RLS-QoL.MethodsScale associations were analyzed at baseline and at the end of maintenance (EoM) using data from the safety set (rotigotine and placebo groups combined [n = 458]). Changes from baseline to EoM in IRLS score vs comparator scale scores also were analyzed.ResultsThere was a trend towards increasing IRLS severity category with increasing CGI-1, RLS-6, and RLS-QoL score. Pearson product moment correlation coefficients showed correlations between IRLS and comparator scale scores at baseline and EoM as well as correlations for change from baseline to EoM.ConclusionCorrelations between the IRLS and comparator scales were substantial. These data indicate that the IRLS is clinically meaningful. The IRLS and CGI-1 are generally sufficient to evaluate the overall severity and impact of RLS symptoms in clinical trials.     

Randomized,placebo-controlled trial of ferric carboxymaltose in restless legs syndrome patients with iron deficiency anemia

ObjectiveIntravenous ferric carboxymaltose (FCM) has been shown to be efficacious in treating restless legs syndrome (RLS) symptoms in non-anemic patients. The aim of this study was to evaluate the effectiveness of FCM in treating RLS symptoms in patients who also had an iron deficiency anemia (IDA).MethodsThis is a randomized, double-blinded, placebo-controlled study. Subjects with RLS and IDA were enrolled. Subjects received an infusion of either 1500 mg FCM or placebo in Phase I. The primary outcomes were a change-from-baseline at week six on the International Restless Legs Syndrome Study Group scale (IRLS). Phase II of the study involved long-term (52 weeks) follow-up, for those who responded to treatment in the prior phase, with the potential for further treatment if symptoms returned.ResultsWe enrolled 29 RLS patients with IDA (15 FCM and 14 placebo). At week six post-infusion, FCM compared to placebo group showed significant improvement from baseline in IRLS score (−13.47 ± 7.38 vs. 1.36 ± 3.59). Among secondary outcome variables, quality of sleep showed significant improvement from baseline in the FCM group. 61% of subjects remained off RLS medications at the Phase II, week-52 endpoint. There were no serious adverse events observed in the study.ConclusionThe study showed significant efficacy and safety of FCM 1500 mg treatment both in the short term (6 weeks) and long term (52 weeks) in RLS patients with IDA.     

Rating of daytime and nighttime symptoms in RLS: validation of the RLS-6 scale of restless legs syndrome/Willis–Ekbom disease

BackgroundThe International Restless Legs Scale (IRLS) is the most widely used of the scales rating the severity of restless legs syndrome/Willis–Ekbom disease (RLS/WED). It has been well validated and is the primary end point for most of the therapeutic and nontherapeutic studies of RLS/WED. It has excellent psychometric properties, although it does not capture the severity of RLS under a wide variety of circumstances and times of day. Moreover, the IRLS has a large placebo effect.MethodsThe Restless Legs Syndrome-6 Scale (RLS-6), however, takes another potentially valuable approach. Six items are rated on a 0–10 scale from no symptoms at 0 to very severe at 10. In addition to questions on satisfaction with sleep and sleepiness, the scale rates the severity of RLS for the past week under four separate circumstances: while falling asleep, during the night, during the day while sitting or lying, and during the day when moving around. The purpose of the current study is to report the validation of the RLS-6 under baseline and therapeutic conditions.ResultsThe RLS-6 seems to be an acceptable, reliable, precise, valid, and responsive instrument for the assessment of RLS severity in a specific and pragmatic manner.ConclusionsAt present, we view the RLS-6 not as a replacement for the IRLS but as a supplement, as each scale provides information not captured by the other.     

Noninvasive Vagus Nerve Stimulation: A New Therapeutic Approach for Pharmacoresistant Restless Legs Syndrome

AimsThis work aimed to study the effect of noninvasive vagus nerve stimulation on severe restless legs syndrome (RLS) resistant to pharmacotherapy.Materials and MethodsPatients with severe pharmacoresistant RLS were recruited from a tertiary care sleep center. Intervention was one-hour weekly sessions of transauricular vagus nerve stimulation (tVNS) in the left cymba concha, for eight weeks. The primary outcome measure was the score on the International Restless Legs Rating Scale (IRLS); secondary outcome measures were quality of life (Restless Legs Syndrome Quality of Life scale [RLSQOL]), mood disorders using the Hospital Anxiety and Depression scale subscale for depression (HADD) and Hospital Anxiety and Depression scale subscale for anxiety (HADA), and objective sleep latency, sleep duration, efficiency, and leg movement time measured by actigraphy.ResultsFifteen patients, 53% male, aged mean 62.7 ± 12.3 years with severe RLS, reduced quality of life, and symptoms of anxiety and depression, were included. The IRLS improved from baseline to session eight: IRLS 31.9 ± 2.9 vs 24.6 ± 5.9 p = 0.0003. Of these participants, 27% (4/15) had a total response with a decrease below an IRLS score of 20; 40% (6/15) a partial response with an improvement in the IRLS > 5 but an IRLS above 20; and 33% (5/15) were nonresponders. After tVNS, quality of life improved (RLSQOL 49.3 ± 18.1 vs 80.0 ± 19.6 p = 0.0005), as did anxiety (HADA 8.9 ± 5.4 vs 6.2 ± 5.0 p = 0.001) and depression (HADD 5.2 ± 4.5 vs 4.0 ± 4.0 p = 0.01). No significant change was found in actigraphic outcome measures.ConclusionsIn this pilot study, tVNS improved the symptoms of RLS in 66% of participants (10/15) with severe pharmacoresistant RLS, with concomitant improvements in quality of life and mood. Randomized controlled trials evaluating therapeutic efficacy of tVNS in RLS are needed to confirm these promising findings.     

An item response analysis of the international restless legs syndrome study group rating scale for restless legs syndrome

BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) is a common central nervous system disorder; however, there is currently a lack of well-validated and easily-administered measures of RLS severity available. The International Restless Legs Syndrome Study Group has recently developed a 10-item scale to meet this need. The International Restless Legs Severity Scale (IRLS) has been shown to have a high degree of reliability, validity, and internal consistency. In order to further demonstrate the validity of the IRLS, the present study examined the relationship between scores on individual IRLS items and overall RLS severity. PATIENTS AND METHODS: The 10-item IRLS was administered to 196 RLS patients. Option characteristic curves (the probability of scoring different options for a given item as a function of overall IRLS score) were generated in order to illustrate the scoring patterns for each item across the range of total RLS severity. Item characteristic curves (the expected score on an item as a function of overall IRLS score) were also generated to illustrate the relationship between scores on the individual items and total RLS severity. RESULTS: The IRLS items demonstrated excellent item response properties, with option and item characteristic curves closely approximating those of an ideal item. Item 3 (relief of arm or leg discomfort from moving around) was the most problematic item in that a 'floor' effect was evident; however, the item response characteristics for this item were still acceptable. CONCLUSIONS: Each IRLS item showed a good relationship between responses on that item and overall RLS severity, providing further evidence for the validity of the IRLS as a measure of RLS severity in RLS patients.     

A randomized,double‐blind,placebo controlled,multi‐center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome

Iron deficiency may exacerbate symptoms in the Restless Legs Syndrome (RLS). We investigated the effect of intravenous iron sucrose or placebo on symptoms in patients with RLS and mild to moderate iron deficit. Sixty patients with primary RLS (seven males, age 46 (9) years, S‐ferritin ≤45 μg/L) recruited from a cohort of 231 patients were randomly assigned in a 12‐months double‐blind, multi‐centre study of iron sucrose 1000 mg (n = 29) or saline (n = 31). The primary efficacy variable was the RLS severity scale (IRLS) score at week 11. Median IRLS score decreased from 24 to 7 (week 11) after iron sucrose and from 26 to 17 after placebo (P = 0.123, N.S. for between treatment comparison). The corresponding scores at week 7 were 12 and 20 in the two groups (P = 0.017). Drop out rate because of lack of efficacy at 12 months was 19/31 after placebo and 5/29 patients after iron sucrose (Kaplan–Meier estimate, log rank test P = 0.0006) suggesting an iron induced superior long term RLS symptom control. Iron sucrose was well tolerated. This study showed a lack of superiority of iron sucrose at 11 weeks but found evidence that iron sucrose reduced RLS symptoms both in the acute phase (7 weeks) and during long‐term follow up in patients with variable degree of iron deficiency. Further studies on target patient groups, dosing and dosing intervals are warranted before iron sucrose could be considered for treatment of iron deficient patients with RLS. © 2009 Movement Disorder Society     

Effect of pramipexole on RLS symptoms and sleep: a randomized, double-blind, placebo-controlled trial

BackgroundPatients with Restless Legs Syndrome (RLS) often seek treatment because of sleep problems related to nocturnal symptoms. Our goal was to test the ability of pramipexole to improve sleep in RLS patients and to reconfirm its efficacy for primary RLS symptoms.MethodsAdults with moderate or severe RLS were randomized to receive placebo or pramipexole (flexibly titrated from 0.25 to 0.75 mg), 2–3 h before bedtime for 12 weeks. The co-primary outcome measures were change in Medical Outcomes Study (MOS) sleep disturbance score and International RLS Study Group Rating Scale (IRLS) score at 12 weeks.ResultsThe intent-to-treat population included 357 patients: 178 received pramipexole and 179 received placebo. At 12 weeks, the adjusted mean change from baseline was greater for pramipexole (vs. placebo) for IRLS score (−13.4 ± 0.7 vs. −9.6 ± 0.7) and MOS sleep disturbance score (−25.3 ± 1.5 vs. −16.8 ± 1.5) (p ⩽ 0.0001; ANCOVA). Responder rates (clinical and patient global impression and IRLS) were also significantly higher in the pramipexole group. RLS-QOL score was improved over placebo at Week 12 (p < 0.01) as were MOS sleep adequacy (p = 0.0008) and quantity (p = 0.08) scores. Nine percent of patients in each group withdrew because of adverse events.ConclusionsPramipexole is effective and well-tolerated for RLS and related sleep disturbance.