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.     

Efficacy and safety of pramipexole in Japanese patients with primary restless legs syndrome: A polysomnographic randomized,double-blind,placebo-controlled study

ObjectiveTo evaluate the efficacy of pramipexole on polysomnographic measures, patient ratings and a clinical rating in Japanese patients with primary restless legs syndrome (RLS).MethodsPatients with moderate to severe RLS having periodic limb movements in bed index (PLMI) ? 5 were randomly assigned to receive pramipexole or placebo in a 6-week, double-blind, placebo-controlled study with forced titration from 0.125 to 0.75 mg/day. Both polysomnography (PSG) and the suggested immobilization test (SIT) were performed at baseline and 6 weeks after starting treatment.ResultsThe analysis of covariance of log-transformed PLMI showed that the adjusted means at the end of study were significantly smaller in the pramipexole group than in the placebo group (p = 0.0019). In all patients, variables on SIT did not show any differences between the two groups, whereas a significant improvement was shown in the pramipexole group compared with the placebo group for patients with a SIT-PLM index at baseline ? 15. Pramipexole group showed a significant reduction in the International Restless Legs Syndrome Study Group rating scale (IRLS; p = 0.0005), a significant improvement in both Patient Global Impression (PGI; p < 0.0001) and Clinical Global Impressions (CGI-I; p = 0.0488), and a significantly greater mean reduction in the Pittsburgh Sleep Quality Index (PSQI; p = 0.0016), when compared with those of placebo group at week 6.ConclusionsPramipexole is highly efficacious in the reduction of PLMI and in the improvement of subjective severity of RLS and subjective sleep disturbance caused by the disorder.     

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.     

Efficacy of vitamins C, E, and their combination for treatment of restless legs syndrome in hemodialysis patients: a randomized, double-blind, placebo-controlled trial

BackgroundRestless legs syndrome (RLS) is a common disorder in hemodialysis patients that leads to insomnia and impaired quality of life. Because high oxidative stress has been implicated in the pathogenesis of RLS, we sought to evaluate the efficacy of vitamins C and E and their combination in reducing the severity of RLS symptoms in hemodialysis patients in this randomized, double-blind, placebo-controlled, four-arm parallel trial.MethodsSixty stable hemodialysis patients who had all four diagnostic criteria for RLS developed by the International Restless Legs Syndrome Group with no acute illness or history of renal stone were randomly allocated to four fifteen-patient parallel groups to receive vitamin C (200 mg) and vitamin E (400 mg), vitamin C (200 mg) and placebo, vitamin E (400 mg) and placebo, and double placebo daily for eight weeks. International Restless Legs Scale (IRLS) scores were measured for all patients at baseline and at the end of treatment phase. The primary outcome was absolute change in IRLS sum score from baseline to the end of treatment phase.ResultsMeans of IRLS sum score decreased significantly in the vitamins C and E (10.3 ± 5.3, 95% CI: 7.4–13.3), vitamin C and placebo (10 ± 3.5, 95% CI: 8.1–11.9), and vitamin E and placebo groups (10.1 ± 6, 95% CI: 6.8–13.5) compared with the double placebo group (3.1 ± 3, 95% CI: 1.5–4.8), (P < 0.001); however, no differences were observed between these treatment groups.ConclusionsVitamins C and E and their combination are safe and effective treatments for reducing the severity of RLS in hemodialysis patients over the short-term.     

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.     

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.     

Investigating the response to intravenous iron in restless legs syndrome: an observational study

ObjectiveTo investigate the effect of intravenous (IV) iron (500 mg ferric carboxymaltose [FCM] as a single dose) on restless legs syndrome (RLS) severity on a day-to-day basis.MethodsTwenty patients with RLS and absolute or functional iron deficiency or low normal serum ferritin (<45 μg/l) were included. Change of RLS severity was evaluated using the International RLS severity scale (IRLS) and the RLS-severity diary (RLS-SD) which evaluates symptom severity over a 6-h period on an 11-point numerical Likert scale, four times a day.ResultsTwelve patients reported that IV FCM improved RLS (“responders”). IRLS score decreased from 30.1 (±5.9) to 23.07 (±9.5) (p = 0.001) in the whole group and from 28.3 (±6.1) to 18.3 (±8.0) (p = 0.002) in the responder group three weeks after IV FCM treatment. A clinically relevant effect of IV iron on RLS severity could be seen as early as day eight. The responder group differed from the non-responder group in tendency by being younger (p = 0.064), having a lower serum ferritin level at baseline (p = 0.097), and presenting a lower number of comorbid conditions.ConclusionsFCM led to a considerable improvement in RLS in the responder group within about one week. These findings are clinically relevant, especially for patients with severe RLS symptoms and iron deficiency, since a change or uptitration of RLS-specific medication can be avoided or postponed in these patients due to the rapid response to IV FCM treatment.     

Is preeclampsia associated with restless legs syndrome?

ObjectiveRestless legs syndrome (RLS) is a common neurologic disorder. Secondary RLS includes pregnancy and iron deficiency. Prevalence of RLS in pregnancy ranges from 11% to 27%. We aimed to assess the frequency and characteristics of RLS in pregnancy in a Peruvian population and to evaluate the possible pregnancy or delivery complications due to RLS.MethodsWe assessed 218 consecutive expectant mothers at the inpatient clinic of the Hospital San Bartolome in Lima, Peru. Assessment was performed by using the standard diagnostic criteria for RLS and by using a clinical and diagnostic interview. Questionnaires for RLS severity, idiopathic RLS (IRLS), and excessive daytime sleepiness (EDS) according to the Epworth sleepiness scale (ESS) were used. Blood examination was performed for hemoglobin and hematocrit. For comparison, RLS patients were matched for age and body mass index (BMI) with pregnant women without RLS.ResultsOut of 218 patients, 40 (18.4%) fulfilled diagnostic criteria for RLS. In RLS patients, prophylactic iron supplementation therapy during pregnancy was less frequently taken (P = .02). Pregnant women with RLS had a higher ESS score than pregnant controls (10.6 +/− 3.1 vs 7.6. +/− 3.6; P < .001). Preeclampsia was more frequent in RLS (7/40 vs 1/39; P = .03).ConclusionsIn our study, RLS was frequent in pregnant Peruvian women, especially in those without prophylactic iron supplementation. RLS patients described more EDS. Preeclampsia was more common in RLS. Our study is the first study to indicate a possible association between RLS and preeclampsia.     

Rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome: A randomized,placebo-controlled polysomnographic study

ObjectiveTo assess the efficacy of rotigotine transdermal patch in subjects with moderate to severe idiopathic restless legs syndrome (RLS) and periodic limb movement (PLM) in sleep in a double-blind, randomized, placebo-controlled, multicenter study (NCT00275236).MethodsSixty-seven (46 rotigotine, 21 placebo) subjects applied rotigotine (maximum 3 mg/24 h) or placebo patches once-daily during a 4-week maintenance period; efficacy evaluations used polysomnographic measures and clinician/patient ratings.ResultsMean PLM index (PLMI; PLM/h time in bed) decreased more with rotigotine (50.9/h to 8.1/h) than with placebo (37.4/h to 27.1/h; adjusted treatment ratio 4.25 (95% CI [2.48, 7.28], p < 0.0001). PLM during sleep with arousal index (PLMSAI; 8.57/h to 2.47/h under rotigotine, 6.5/h to 4.95/h under placebo; adjusted treatment difference: ?3.12 (95% CI [?5.36, ?0.88], p = 0.0072) also improved more under rotigotine. At end of maintenance, 39% of rotigotine subjects had PLMI levels <5/h and 26% showed no RLS symptoms (IRLS = 0), whereas no placebo subject met these criteria. Common drug-related adverse events for rotigotine and placebo included nausea (21.7%/4.8%), headache (17.4%/14.3%), application site reactions (17.4%/4.8%), and somnolence (10.9%/9.5%); most were mild to moderate in intensity.ConclusionsRotigotine transdermal patch was efficacious and well tolerated in the short-term treatment of RLS motor symptoms and associated sleep disturbances.     

Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study

Background and PurposeRestless Legs Syndrome (RLS) is a primary disorder of sensation that affects sleep and has been associated with iron deficiency. The purpose of this study was to determine if symptomatic RLS patients with low-normal serum ferritin levels benefit from oral iron replacement.Patients and MethodsThis was a randomized, placebo-controlled, double-blinded study. Eligible patients were randomized to oral iron therapy vs. appearance-matched placebo and followed over a 12 week period.ResultsBaseline International Restless Leg Scale (IRLS) scores for the treatment (24.8 ± 5.72) and placebo (23.0 ± 5.03) groups were similar. Baseline ferritin levels for the treatment (40.6 ± 15.3 ng/ml) and placebo (36.7 ± 20.8 ng/ml) groups were also similar. After 12 weeks, IRLS scores decreased more in the treatment arm (10.3 ± 7.40) than in the placebo arm (1.14 ± 5.64), (p = 0.01). Ferritin levels increased more in the treatment arm (25.1 ± 20.3 ng/ml) than in the placebo arm (7.5 ± 13.7 ng/ml), (p = 0.04). We observed a nonsignificant trend toward improved quality of life in the treated patients, (p = 0.07).ConclusionsThis is the first double-blinded, placebo-controlled study to demonstrate statistically significant improvement in RLS symptoms using oral iron therapy in patients with low-normal ferritin. The findings from this study suggest that additional larger randomized placebo-controlled trials of iron as treatment for patients with low-normal ferritin are warranted.     

The severity range of restless legs syndrome (RLS) and augmentation in a prospective patient cohort: Association with ferritin levels

ObjectivesThe aim of the study was to prospectively examine all patients with a diagnosis of RLS consulting a sleep disorders clinic and to assess RLS severity and augmentation and their associations, including ferritin levels.MethodsPatients were stratified into patients with RLS as ancillary diagnosis, RLS sufferers without current augmentation and RLS sufferers with current augmentation. Work-up included RLS severity scales and blood biochemical variables including indices of iron metabolism.ResultsIn an 18-month period, 302 patients with RLS (183 women, 119 men; mean age, 59.1 ± 13.7 years) were recruited. RLS was considered idiopathic in 291 patients (96.4%). Most patients (240, 79.5%) were RLS sufferers, whereas the remaining 62 (20.5%) had RLS as ancillary diagnosis. Nineteen out of 162 patients treated with dopaminergic agents (11.7%) had current augmentation. Almost one-third of all patients (31.1%) had ferritin levels <50 μg/l. Patients with an ancillary diagnosis of RLS had higher ferritin levels than RLS sufferers without current augmentation. The lowest ferritin levels were present in RLS sufferers with current augmentation 132.8 ± 98.0 μg/l vs. 100.6 ± 84.5 μg/l vs. 55.8 ± 43.6 μg/l; p = 0.002). Patients with augmentation did not differ from non-augmented patients regarding age, gender, RLS etiology, presence of previous augmentation, or any other documented comorbidity (p > 0.05).ConclusionThe severity spectrum of RLS in this clinical cohort ranged from the ancillary diagnosis of RLS to augmented RLS. There was an inverse correlation between RLS severity and ferritin levels. Patients with current augmentation had the lowest ferritin levels. Our data further strengthen a putative role of low iron stores as a potential aggravator of idiopathic RLS. Moreover, low ferritin might represent a potential biomarker of RLS augmentation under dopaminergic therapy.     

Assessing health-related quality of life in patients with restless legs syndrome in Korea: Comparison with other chronic medical diseases

BackgroundThere have been few quality of life (QoL) studies of patients with restless legs syndrome (RLS) in Asian countries. We studied the QoL of patients with RLS and compared it to normal controls and patients with hypertension, type 2 diabetes, or osteoarthritis in Korea.MethodsA total of 215 RLS patients (141 female; mean age 51.7 ± 13.5) were enrolled. All patients completed the questionnaires, including all the Korean versions of SF-36, RLS QoL, the International RLS Severity scale (IRLS), the Pittsburgh Sleep Quality Index (PSQI), and the Beck Depression Inventory-2 (BDI-2). These results were compared with the scores from normal controls (N = 214) and from patients with hypertension (196), uncomplicated type 2 diabetes (185), or osteoarthritis of the knee (177).ResultsThe SF-36 QoL in patients with RLS was lower than that of the normal controls, and even lower than patients with hypertension or diabetes, but higher than those with osteoarthritis. The SF-36 Qol of RLS patients showed a significantly negative correlation with the severity of RLS symptoms (r = ?0.430, p < 0.001) and the severity of depression (r = ?0.565, p < 0.001), but was not significantly related to gender, age, or age-of-symptom onset (early or late-onset). Step-wise multiple regression identified three factors related to SF-36 QoL: depression (46.5% of RLS had responses on BDI-2 indicating depression) (β = ?.899, p < 0.001), RLS symptom severity (K-IRLS) (β = ?.718, p < 0.001), and gender (female) (β = ?6.128, p = 0.007).ConclusionsThese findings show that RLS has a considerable impact on the QoL of Koreans, which is comparable with studies of western countries. The QoL impairment relates to the degree of depression with RLS for Koreans.     

A dose-ranging study of pramipexole for the symptomatic treatment of restless legs syndrome: Polysomnographic evaluation of periodic leg movements and sleep disturbance

Objective: To evaluate, both polysomnographically and by subjective scales, the efficacy and safety profile of pramipexole for restless legs syndrome (RLS) via a 3-week, double-blind, placebo-controlled, parallel-group, dose-ranging study.Methods: At baseline and after 3 weeks, periodic limb movements (PLM) and sleep parameters were assessed by polysomnography, and patients self-assessed their sleep disturbance and overall RLS severity using the international RLS study group rating scale (IRLS). Four pramipexole doses were evaluated: 0.125, 0.25, 0.50, and 0.75 mg/d. Data from 107 patients were included in the intent-to-treat (ITT) analysis.Results: For pramipexole recipients, the primary outcome measure, PLM per hour in bed asleep or awake (the PLM index, or PLMI), decreased by a median of ?26.55 to ?52.70 depending on dosage group, vs. ?3.00 for placebo (p < 0.01 or ?0.001 for each group vs. placebo; Wilcoxon–Mann–Whitney test). Improvements in the secondary endpoints of PLM while asleep and while awake were also significantly superior for pramipexole. At 3 weeks, all pramipexole doses reduced the median for PLM while asleep to levels considered normal (<5 PLM/h). Except for delta-sleep time and awakenings/arousals, sleep parameters remained unchanged or favored pramipexole. Median sleep latency was reduced by ?5.00 to ?11.75 min in the pramipexole groups, vs. ?2.00 for placebo (p < 0.05 for all groups except 0.25 mg/d). Median total sleep time increased by 25.75–66.75 min, vs. 25.50 (p < 0.05 for 0.50 mg/d), and median time in stages 2–4/rapid eye movement (REM) sleep increased by 37.00–68.00 min, vs. 26.75 (p < 0.05 for 0.50 mg/d). By subjective IRLS ratings, all pramipexole doses were significantly superior to placebo. Safety analysis demonstrated no dose-dependent increase in adverse events, and no drug-related increase in daytime somnolence was observed.Conclusions: Pramipexole is effective and well tolerated in RLS, most notably among objective measures, for reducing PLM and decreasing sleep latency. Although other sleep parameters showed lesser, usually insignificant change, patients’ subjective ratings of RLS severity and sleep disturbance were significantly improved (p ? 0.0023).     

Pregabalin increases slow-wave sleep and may improve attention in patients with partial epilepsy and insomnia

Insomnia is a common phenomenon particularly in patients with epilepsy. This study was performed to look at the effects of pregabalin, an anticonvulsant known to increase sleep depth and decrease arousals, in patients with insomnia and well-controlled epilepsy.MethodsThis was a double-blind, placebo-controlled, crossover study of subjects with insomnia and epilepsy. Each subject was treated with pregabalin 150 mg BID or placebo for two weeks, followed by a two-week washout period, then the other treatment for two weeks. Polysomnography and neuropsychological testing were performed at baseline and at the end of each treatment arm.ResultsThere was a significant increase in percentage of slow-wave sleep and a decrease in stage 1 sleep when subjects were taking pregabalin. Sleep efficiency increased during pregabalin treatment, although this was not statistically significant (84.5 +/? 4.6% for placebo versus 90.4 +/? 2.6% for pregabalin). There were a significant improvement in attention in the pregabalin group based on trial one of the Rey-Auditory Verbal Learning Test and a trend toward improvement in the psychomotor vigilance task; other neuropsychological measures were not significantly changed.ConclusionConcurrent treatment with pregabalin improves sleep depth in patients with insomnia and epilepsy and improves daytime attention.     

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.     

A phase II,open-label,non-comparative study of Botulinum toxin in Restless Legs Syndrome

ObjectiveTo assess the efficacy of intradermally injected botulinum neurotoxin type A (BoNT/A) in patients with Restless Legs Syndrome (RLS).MethodsWe conducted an optimal two-stage, phase II exploratory, open label, non-comparative clinical trial. The primary outcome measure was the efficacy of BoNT/A defined by the proportion of patients (responders) with ?50% improvement of their RLS severity score at week 2 following injections compared to baseline score at inclusion. Twenty-seven patients were to be included in the first stage of the trial, which was to be stopped if less than nine responders were documented. Selected patients had a minimum score of 21 on the International RLS Rating Scale. They all received a series of 20 intradermal injections of 0.05 ml of BoNT/A in symptomatic areas in their lower limbs. Change of RLS severity was evaluated over a 6 months period.ResultsOf the 27 selected patients, only six achieved the primary endpoint at week 2. In these six patients, the median duration (Inter-Quartile Range) of the IRLSRS score improvement of at least 50% was 46 days (42–126).ConclusionsConsidering the proportion of responders as the primary endpoint of this trial, BoNT/A showed no efficacy in alleviating RLS sensory symptoms.     

Lower molecular weight intravenous iron dextran for restless legs syndrome

BackgroundVarious techniques used to assess brain iron concentrations have demonstrated the presence of low iron stores in patients with restless legs syndrome (RLS). Previous open-label and randomized studies generally support the value of iron treatment for RLS symptoms. Only one of these studies assessed iron therapy response to changes in brain iron status. The current study was designed to assess the effect of iron therapy on RLS symptoms and on CSF measures of brain iron status.MethodsIdiopathic RLS patients drawn from the Korean population received four weekly intravenous (IV) doses of 250 mg low-molecular weight iron dextran for a total dose of 1 g. One week after the last dose, any subject on RLS medication tapered off the RLS medications. Blood and CSF samples were taken to measure iron parameters at baseline and again, three weeks after the last dose. We have been following their response to the drug for two years after treatment.ResultsTwenty-five patients (age 55.2 ± 9.3, 18 female) enrolled in this study without serious adverse reactions. Seventeen of the 25 patients (68%) showed moderate or complete improvement of all RLS symptoms after treatment based on the Korean-translated versions of the International RLS Severity scale (K-IRLS). Changes in the K-IRLS did not correlate significantly with changes in CSF ferritin. The response to IV iron could not be predicted by patients’ demographics, or by blood or CSF iron baseline characteristics. RLS symptom improvement started between one and six weeks after treatment and the treatment benefits lasted from one month to 22 months. Fourteen patients, (56%) completely stopped all medications, for a mean duration of 31.3 ± 33.1 weeks. These results are comparable to those from a prior study with high molecular weight dextran.ConclusionsIntravenous low-molecular weight iron dextran produced significant improvement of RLS symptoms in a majority of patients without any significant adverse effects. Serious anaphylaxis occurs with high molecular weight, but rarely, if ever, with this low molecular weight dextran. Given apparent comparable efficacy the low molecular weight and not the high molecular weight iron dextran, should be considered for RLS treatment. Although changes in CSF ferritin were seen following therapy, these changes were not related to clinical improvements.     

Effects of pregabalin on behavioral alterations induced by ketamine in rats

Objective:The aim of this study is to investigate the effects of pregabalin on the behavior of rats under the influence of ketamine, an NMDA receptor antagonist that mimics the symptoms of schizophrenia.Methods:Rats were injected with saline or 25 mg/kg ketamine intraperitoneally. After that, behavior modifications were investigated by the evaluation of stereotypy and hyperlocomotion, after treating rats with pregabalin (at doses of 30 mg/kg or 100 mg/kg) or placebo (saline solution).Results:The administration of pregabalin reduced ketamine-induced hyperlocomotion. However, neither doses of pregabalin had a significant effect on ketamine-induced stereotypy.Conclusion:This is the first study to investigate the effects of pregabalin using an animal model of psychosis. Furthermore, our results indicate that behavioral changes induced by ketamine in rats can be reversed with the use of pregabalin, suggesting its potential to treat psychotic symptoms.     

The effects of pregabalin on sleep disturbance symptoms among individuals with fibromyalgia syndrome

ObjectivesSleep disturbances are common in patients with fibromyalgia (FM). The objective of this analysis was to evaluate the effects of pregabalin on sleep in patients with FM.MethodsAnalyses were based on two randomized, double-blind, placebo-controlled trials of pregabalin (300 mg, 450 mg, and 600 mg daily) in adult FM patients. Sleep outcomes included the Medical Outcomes Study (MOS) Sleep Scale and a daily diary assessment of sleep quality. Treatment effects were evaluated using analysis of covariance. Clinically important differences (CID) in the Sleep Quality Diary and MOS Sleep Disturbance scores were estimated using mixed-effects models of changes in scores as a function of patients’ global impressions of change. Mediation modeling was used to quantify the direct treatment effects on sleep in contrast to indirect influence of the treatment on sleep via pain.ResultsA total of 748 and 745 patients were randomized in the respective studies. Patients were predominantly Caucasian females, average age 48–50 years, on average had FM for 9–10 years, and experienced moderate to severe baseline pain. Pregabalin significantly improved the Sleep Quality Diary (P < 0.001), MOS Sleep Disturbance (P < 0.01), MOS Quantity of Sleep (P < 0.003), and MOS Sleep Problems Index scores (P < 0.02) relative to placebo. Treatment effects for the 450 mg and 600 mg groups exceeded the estimated CID thresholds of 0.83 and 7.9 for the Sleep Quality Diary and MOS Sleep Disturbance scores, respectively. Mediation models indicated that 43–80% of the benefits on sleep (versus placebo) were direct effects of pregabalin, with the remainder resulting from an indirect effect of treatment via pain relief.ConclusionsThese data demonstrate improvement in FM-related sleep dysfunction with pregabalin therapy. The majority of this benefit was a direct effect of pregabalin on the patients’ insomnia, while the remainder occurred through the drug’s analgesic activity.