Psychological distress of patients suffering from restless legs syndrome: a cross-sectional study.

BACKGROUND: Restless legs syndrome (RLS) is a chronic disorder with substantial impact on quality of life similar to that seen in diabetes mellitus or osteoarthritis. Little is known about the psychological characteristics of RLS patients although psychological factors may contribute to unfavourable treatment outcome. METHODS: In an observational cross-sectional design, we evaluated the psychological features of 166 consecutive RLS patients from three outpatient clinics, by means of the Symptom Checklist 90-R (SCL-90-R) questionnaire. Additionally, the Beck Depression Inventory-II (BDI-II) and the International RLS Severity Scale (IRLS) were measured. Both treated and untreated patients were included, all patients sought treatment. RESULTS: Untreated patients (n = 69) had elevated but normal scores on the SCL-90-R Global Severity Index (GSI; p = 0.002) and on the sub-scales somatisation (p < 0.001), compulsivity (p = 0.003), depression (p = 0.02), and anxiety (p = 0.004) compared with a German representative sample. In the treated group, particularly in those patients who were dissatisfied with their actual treatment (n = 62), psychological distress was higher than in the untreated group with elevated scores for the GSI (p = 0.03) and the sub-scales compulsivity (p = 0.006), depression (p = 0.012), anxiety (p = 0.031), hostility (p = 0.013), phobic anxiety (p = 0.024), and paranoid ideation (p = 0.012). Augmentation, the most serious side effect of dopaminergic, i.e. first-line treatment of RLS, and loss of efficacy were accompanied with the highest psychological distress, as seen particularly in the normative values of the sub-scales compulsivity and anxiety. Generally, higher RLS severity was correlated with higher psychological impairment (p < 0.001). CONCLUSION: Severely affected RLS patients show psychological impairment in multiple psychological domains which has to be taken into account in the treatment regimen.

Levodopa for restless legs syndrome.

BACKGROUND: Levodopa plus dopamine decarboxylase inhibitor is a common treatment for restless legs syndrome (RLS). OBJECTIVES: To evaluate efficacy and safety of levodopa for RLS compared to placebo and other active agents. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2008, Issue 4), MEDLINE, EMBASE, PsycINFO and CINAHL, from January 1985 to December 2008, reference lists of articles, and contacted pharmaceutical companies. SELECTION CRITERIA: We included double-blind randomised controlled trials (RCT) investigating levodopa treatment versus placebo or other treatment for at least seven days in patients with RLS (age ≥ 18 years). Outcomes included symptom severity, CGI-I, objective as well as self rated sleep parameters, quality of life, and safety parameters. DATA COLLECTION AND ANALYSIS: Two authors extracted data, assessed risk of bias, and contacted pharmaceutical companies and authors for additional information. We collected dropouts due to adverse events and patients experiencing adverse events. MAIN RESULTS: Six placebo controlled and three active controlled RCTs were included (521 participants). Symptom severity (11 point rating scale, 0 points indicating no symptoms, 10 points indicating maximally severe symptoms) was more reduced with levodopa than placebo in two studies (mean difference (MD) -1.34, 95% confidence interval (CI) -2.18 to -0.5, P = 0.002). Periodic limb movements in sleep per hour of sleep (PLMS-Index; PLMSI) improved by -26.28/h compared to placebo (95% CI -30.53 to -22.02, P < 0.00001).The CGI-I changed more with levodopa than placebo in two studies (MD -1.25, 95% CI -1.89 to -0.62, P = 0.0001). In two studies, sleep quality (sleep questionnaire, visual analogue scale) showed a large effect (standardised mean difference (SMD) 0.92, 95% CI 0.52 to 1.33, P < 0.00001) whereas quality of life (50 mm Visual Analogue Scales) improved by 3.23 compared to placebo (95% CI 1.64 to 4.82, P < 0.0001). Few patients dropped out of treatment (3 of 218 patients) but more levodopa treated patients experienced adverse events than with placebo (odds ratio 2.61, 95% CI 1.35 to 5.04, P = 0.004). Two dopamine agonist controlled studies showed smaller effects with levodopa than cabergoline and pramipexole on the IRLS (MD 5.25, 95% CI 2.10 to 8.40, P =0.001), CGI-I (MD 0.62, 95% CI 0.37 to 0.87, P < 0.00001), and quality of life (MD 5.54, 95% CI 2.65 to 8.43, P = 0.0002). AUTHORS' CONCLUSIONS: Levodopa is efficacious for the short-term treatment of RLS. Augmentation, the clinically most relevant adverse event, was not investigated sufficiently.

Dopamine agonists for restless legs syndrome.

BACKGROUND: According to clinical guidelines, dopamine agonists are the first-line treatment of restless legs syndrome (RLS). OBJECTIVES: To evaluate efficacy and safety of dopamine agonists for RLS. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, Issue 4), MEDLINE, EMBASE, PsycINFO and CINAHL, from January 1985 to December 2008, plus reference lists of articles. We contacted pharmaceutical companies. SELECTION CRITERIA: We included double-blind randomised controlled trials (RCTs) of dopamine agonist treatment versus placebo or other treatment for a period of at least seven days in patients with RLS (≥ 18 years). Outcomes included the International RLS Severity Rating Scale (IRLS), Clinical Global Impressions (CGI-I), polysomnography and self rated sleep quality, quality of life, daytime functioning, and safety parameters. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data separately; assessed risk of bias; and contacted pharmaceutical companies and authors for additional information. We collected dropout rates due to adverse events and experience of adverse events. MAIN RESULTS: We included 35 placebo controlled and three active controlled RCTs (N = 7365). The mean reduction on the IRLS was -5.7 points lower in dopamine agonist treatment compared to placebo (95% confidence interval (CI) -6.7 to -4.7). Periodic limb movements in sleep per hour of sleep (PLMS-Index; PLMSI) were -22.4/h lower than in placebo (95% CI -27.8 to -16.9). Self rated quality of sleep and disease specific quality of life were improved by a standardised mean difference (SMD) of 0.40 (95% CI 0.33 to 0.47) and 0.34 (95% CI 0.23 to 0.44), respectively. Patients were more likely to drop out (odds ratio (OR) 1.82, 95% CI 1.35 to 2.45) and experienced more adverse events under dopamine agonist treatment than with placebo (OR 1.82, 95% CI 1.59 to 2.08). Visual inspection of forest plots showed the highest efficacy in three studies investigating cabergoline and pergolide (N = 3). Active controlled trials investigated effects of cabergoline, pergolide, and pramipexole in a number of outcomes. The IRLS score was lower with cabergoline and pramipexole compared to levodopa (MD -5.3, 95% CI -8.4 to -2.1). Only four studies investigated treatment efficacy up to seven months. The most severe side effect, augmentation, was not assessed reliably. AUTHORS' CONCLUSIONS: The meta-analyses show the superiority of dopamine agonists over placebo in RCTs up to seven months. Cabergoline and pramipexole showed larger efficacy compared to levodopa in some but not all outcomes.

What treatment works best for restless legs syndrome? Meta-analyses of dopaminergic and non-dopaminergic medications.

BACKGROUND: At the time of writing only dopamine agonists are licensed for the treatment of restless legs syndrome (RLS) in various countries, but randomized controlled trials (RCTs) have been performed with other treatments. We performed comprehensive meta-analyses and indirect comparisons of RCTs for all currently recommended treatments of RLS. METHODS: We searched the Central, Medline, Embase, PsycINFO and CINAHL databases. Outcome measures were the international RLS study group severity scale (IRLS), clinical global impression-improvement, (CGI-I), periodic limb movement index (PLMI), and psychosocial parameters such as quality of life (QoL). We also conducted indirect comparisons by testing for heterogeneity between the substance groups. RESULTS: Placebo (58 trials) and actively (4 trials) controlled RCTs with dopamine agonists (38 trials), levodopa (4 trials), anticonvulsants (13 trials), most of them with α2δ ligands (11 trials), opioids (1 trial), and iron treatments (6 trials) were included (9596 patients). Although treatment effects showed large variations, changes in the IRLS in the substance groups were comparable (P = 0.78), with a mean reduction in the IRLS of -5.47 points for dopamine agonists, -5.12 points for anticonvulsants (α2δ ligands and levetiracetam), and -4.59 points for iron treatments. The CGI-I indicated slightly different treatment effects between the substance groups, while PLMI changes during treatment differed (P = 0.002), showing a marked decrease with dopamine agonists (-22.50/h), levodopa (-26.01/h), and oxycodone (-34.46/h) compared with a slight decrease for anticonvulsants (α2δ ligands and levetiracetam; -8.48/h) and iron treatments (-13.10/h). Quality of sleep and QoL improved moderately in most of the RCTs investigating these parameters (standardized mean difference, SMD) 0.40 and 0.33, respectively). In the few studies evaluating the change of depressive (n = 4) or anxiety symptoms (n = 3), these symptoms improved slightly (SMD -0.24, and -0.21). Adverse effects and dropouts were comparable in number across all substance groups. In meta-regressions, the treatment effect was predicted by the design of the trial (the more sites involved in a trial the lower the effect) and by the duration of action of a medication (the longer the duration of action, expressed as the half-life time of a substance, the greater the improvement), the latter indicating potential superiority of treatments with stable blood concentration. CONCLUSION: This first meta-analysis of all RCTs for the pharmacological treatment of RLS provides evidence that, besides the well-defined efficacy of dopaminergic treatment, other treatments with different pharmacological principles show efficacy in small samples and may be well-tolerated alternatives for the treatment of RLS. In the group of anticonvulsants, only the trials performed with α2δ ligands such as gabapentin, gabapentin enacarbil, and pregabalin showed good efficacy. This indicates a specific mechanism of action of these substances in RLS. The group of iron treatments consisted of a few trials with different compounds in oral and intravenous application form, respectively. For a more differentiated evaluation of the efficacy of iron treatments further studies are necessary. The large efficacy of one opioid RCT in RLS has to be confirmed in further studies.

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

OBJECTIVE: To 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. METHODS: Twenty 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. RESULTS: Twelve 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. CONCLUSIONS: FCM 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.

Efficacy and safety of dopamine agonists in restless legs syndrome.

OBJECTIVE: Restless legs syndrome (RLS) is a common neurological disorder causing considerable impairment to daily living. This article is an overview of a comprehensive Cochrane meta-analysis on the efficacy and safety of dopamine agonists (DAs), the first-line treatment of RLS. METHODS: CENTRAL, MEDLINE, EMBASE, PsycINFO, and CINAHL databases were searched for double-blind randomized controlled trials (RCTs) of DAs vs placebo. RESULTS: Thirty-five placebo-controlled RCTs (total number of patients=6954) were eligible. The likelihood of bias was considered to be low. The mean treatment duration of the RCTs was 10.3 (standard deviation 7.3) weeks, with treatment durations up to seven months. Overall, DAs showed a moderate improvement in the International RLS Severity Scale score (mean difference -5.7 points [95% confidence interval, CI, -6.7 to -4.7; P<0.00001]) and the Clinical Global Impression-Improvement response (risk ratio 1.44 [95% CI 1.34-1.54; P<0.00001]) compared with placebo. Periodic limb movements decreased by -22.38/h (95% CI -27.8 to -16.9; P<0.00001) for DAs compared with placebo. Sleep quality and disease-specific quality of life increased slightly to moderately. Safety data confirmed the established safety characteristics of DAs. Augmentation, a specific side-effect of dopaminergic treatment of RLS, was not assessed adequately. CONCLUSIONS: This meta-analysis showed that DAs have moderate efficacy in the treatment of RLS. Actively controlled and long-term studies are still lacking. Large-scale comparative studies are needed to identify the most efficient treatments for this chronic disorder.