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Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Nov. (Comparative Effectiveness Reviews, No. 86.)

Results

Literature Search

Results of the literature search and screening process are shown in Figure 2. We identified 671 unique publications. Title and abstract screening resulted in 138 potentially relevant publications. Full-text screening resulted in 53 studies that fulfilled eligibility criteria and were included: of these 33 were randomized controlled trials (RCTs) (31 placebo or usual care controlled) and 18 were observational studies (including open-label extensions of included RCTs) that reported long-term treatment withdrawals, reasons for withdrawals, or percentage of patients developing augmentation. All RCTs that examined pharmacologic treatments were industry sponsored.

Figure 2 is the literature flow diagram. It describes the literature search and screen processes which is also described in the report text.

Figure 2

Flow diagram of search strategy. RCT = randomized controlled trial

Description of Included Studies

Of the 53 studies included1720,2237,4244,4859,6167,81,82, 33 placebo-controlled RCTs15,1844,46,47,66,67,82 and two 16,17 direct comparison RCTs provided efficacy and harms data, and 18 observational studies4859,6165,81 contributed data on long-term harms (Appendix F). Of the 33 RCTs included, 31 evaluated pharmacological treatments1517,2230,3244,46,47,58,66,67,82 and three evaluated nonpharmacologic treatments.1820 Pharmaceutical agents evaluated were dopamine agonists (19),17,2230,3239,58 alpha-2-delta ligands (7),40,4244,46,82 and iron therapy (2).66,67 Dopamine agonists evaluated were ropinirole (7),22,23,27,29,35,36,38 pramipexole (5),24,26,28,32,37 rotigotine (4),25,31,34,39 and cabergoline (3).17,30,33 Anticonvulsant alpha-2-delta ligands were prodrug gabapentin enacarbil (3),40,41,43,82 pre-gabalin (2),42,44 or gabapentin.43 Miscellaneous pharmacologic treatments included intravenous iron15 and antidepressant bupropion.47 Nonpharmacologic studies evaluated exercise (1),19 near-infrared light (1),21 a botanical extract of the herb valerian (1),20 and a pneumatic compression device (1).18 Except for the two small trials of iron therapy66,67 and the three trials evaluating nonpharmacologic treatments1820, all trials were industry sponsored.

Studies typically enrolled adults age 18 to 70 or 80 and used extensive exclusion criteria, specifically excluding pregnant women or those at risk for pregnancy and those with severe liver or renal disease. Additional frequent exclusions involved patients who had previously been taking restless legs syndrome (RLS) drugs and or had adverse events or failure to respond. Studies did not report comorbidities. Most studies required an International Restless Legs Syndrome (IRLS) scale score of ≥15 (at least “high moderate” severity) and frequent symptoms (>2 to 3 times/week) for a prolonged period. Three studies27,34,35 enrolled patients with IRLS scale scores of >20 (severe or very severe). One small study (n=22)42 enrolled subjects with an IRLS scale score of >10.

We did not include studies of the drug cabergoline (an ergot-derived dopamine agonist) in our main analysis, because cabergoline is little used, has been shown to increase the risk for cardiac valvular disorders and is not FDA approved for treatment of RLS. We analyzed 25 placebo-controlled RCTs and one active controlled RCT for efficacy outcomes. Our pooled analysis included 16 studies of dopamine agonists and six studies of anticonvulsant alpha-2-delta ligands.

Study Quality and Publication Bias

We report our assessment of individual study trial quality in Appendix D. Nearly all of the pharmacologic trials (dopamine agonist, anticonvulsants, and iron therapies) were of good quality or had low risk of bias. Blinding of participants and investigators was reported for every trial with the exception of the study assessing exercise.19 Allocation concealment was adequate in most trials. Intention to treat analysis, as defined as analyzing patients on the basis of the treatment they were originally allocated to, was often not done in the dopamine agonist trials. Treatment and/or post-baseline data were often required for the efficacy analyses. Nearly all of the included studies adequately described reasons for study withdrawal. All of the pharmacologic trials received funding from industry and two trials noted that the study sponsor was involved in the study design and data analysis and interpretation.31,34 We assessed for publication bias by constructing funnel plots of dopamine agonist trials that reported mean change in IRLS total scores. We attempted to minimize publication bias by using multiple search strategies and databases, handsearching references and soliciting input about potentially key studies from our Technical Expert Panel members. A funnel plot of all the 12 placebo-controlled dopamine agonist trials reporting mean change in the IRLS total score from baseline showed no asymmetry (Egger intercept 2-sided p=0.35). (Appendix F)

Key Question 1. What is the comparative effectiveness of treatments for restless legs syndrome (RLS)?

  1. What are the benefits from RLS treatments when compared with placebo or no treatment?
  2. What are the benefits from RLS treatments when compared with other active treatments?
  3. What is the durability and sustainability of treatment benefits?

Key Points

  • RCT results were limited to short-term efficacy studies versus placebo or usual care (≤6 months).
  • Compared to placebo, dopamine agonists (ropinirole, pramipexole, and rotigotine) increased the percent of patients with a clinically important response (≥50% reduction in IRLS symptom scale scores or who were “improved” or “much improved” on patient or clinician-reported global impressions scale), reduced RLS symptoms, and improved disease-specific quality of life and patient-reported sleep outcomes (high-strength evidence).
  • Alpha-2-delta ligands, gabapentin enacarbil, and pregabalin, increased the percentage of patients with a clinically important response (≥50% reduction in IRLS), improved clinician-reported global impressions (high-strength evidence), disease-specific quality of life and other patient-reported sleep outcomes compared to placebo (low-strength evidence). Gabapentin enacarbil improved sleep adequacy based on the medical outcome scale (MOS)-sleep adequacy domain (high-strength evidence).
  • We found no clear evidence of a dose effect for the outcomes of IRLS responders or mean change in IRLS scale scores for either dopamine agonists or alpha-2-delta ligands.
  • There is limited indirect comparison evidence that the effect on clinically important response may vary somewhat by specific type of dopamine agonist or alpha-2-delta ligand.
  • Intravenous ferric carboxymaltose slightly improved IRLS symptom scale scores and disease-specific quality of life compared to placebo (moderate-strength evidence) and improved patient-reported sleep outcomes (low-strength evidence) in patients without iron deficiency.15
  • No eligible studies assessed opioids, sedative hypnotics, or tramadol, though these are used clinically for RLS treatment.
  • One small crossover trial found no significant improvement in IRLS scores with dopamine agonist pramipexole treatment compared to dual release levodopa/benserazide therapy (low-strength evidence).16 One study17 found that the dopamine agonist cabergoline improved scores on the IRLS symptom scale and RLS quality of life scale more than Levodopa (moderate-strength evidence).
  • Four small RCTs1821 addressed nonpharmacologic interventions. Pneumatic compression devices18 reduced IRLS symptom scale scores more than sham (moderate-strength evidence). Near-infrared light treatment improved IRLS symptom scores more than sham (low-strength evidence).21 Strength training and treadmill walking19 improved IRLS symptoms but adherence was poor (low-strength evidence). The botanical extract valerian20 was not effective (low-strength evidence).
  • Applicability to broader populations may be limited because studies enrolled middle-aged adults who were nonpregnant and primarily white and who had few comorbidities and RLS symptoms that were long term, frequent, and high-moderate to very severe.
  • Observational studies and long-term open-label followup from RCTs of pharmacologic interventions found that treatment withdrawal due to lack of efficacy at 1 year or more ranged from 6 to 32 percent.

Dopamine Agonists

Efficacy of dopamine agonists was evaluated in 18 randomized, double-blind, placebo-controlled studies2238 and two comparative effectiveness studies.16,17 Two of the placebo-controlled studies30,33 and the only comparative effectiveness trial assessed the dopaminergic analog cabergoline17 which is not FDA approved for treatment of RLS and is rarely used in the United States. We do not include outcomes or characteristics of the two cabergoline placebo controlled studies 30,33. We do describe the findings of the comparative effectiveness trial of cabergoline versus levodopa because the primary intent of this report is a comparative effectiveness review.17

Only two placebo controlled trials lasted 24 weeks or more,26,34 and none exceeded 28 weeks. The mean age of participants was 55 years, and women constituted 65 percent (range 55 to 74) of randomized participants. Participants were overwhelmingly white in the seven trials that reported race/ethnicity.23,24,25,28,32,34,37

Two additional randomized trials assessed cabergoline. All studies used the IRLS criteria to diagnose RLS (Table 4). Most studies required at least high-moderate symptom severity with frequent symptom occurrence and duration of at least 1 month. Patients were typically excluded if they were pregnant, contemplating becoming pregnant, or had psychiatric disorders, substance use, or other serious medical conditions, including renal insufficiency. Mean symptom severity was severe at baseline for all trials assessed using the IRLS scale score (mean=25.1). RLS duration varied with a mean of 17 years for ropinirole to 2 years for rotigotine trials. Trials enrolled newly diagnosed and not previously treated patients and those who had received prior RLS treatments. On average, over one half (60%) of patients in the rotigotine trials had received previous RLS treatment, versus 26 percent and 44 percent respectively for pramipexole and ropinirole. Seven trials excluded patients with augmentation/end-of-dose rebound during previous RLS treatment. Study drugs were given orally on a daily (rather than “as needed”) basis, with the exception of rotigotine, which was delivered transdermally each day. Most studies used flexible up-titration, with utilized doses ranging from 0.125 to 0.75 mg/day for pramipexole, 0.25 to 4 mg/day for ropinirole, and 1 to 3 mg/day for rotigotine. Four studies investigated multiple fixed doses of drug treatments in separate study arms.

Table 4. Outcomes evaluated in placebo studies of dopamine agonists.

Table 4

Outcomes evaluated in placebo studies of dopamine agonists.

Study and patient characteristics (Tables 46) that we evaluated were fairly similar across the dopaminergic agents except the following: (1) study length: rotigotine trials had longest duration of followup (mean=21.2 weeks), (2) duration of RLS symptoms: subjects in ropinirole trials had longest mean symptom duration (19.1 years), and (3) previous RLS treatment: the percentage of subjects receiving prior RLS pharmacological treatment was lowest in pramipexole studies (21.0%). There was evidence of incomplete outcome reporting (Table 4). All 16 studies reported on mean change from baseline in the IRLS total score. Thirteen studies provided data sufficient for pooling. The second most frequently reported outcome was the Clinical Global Impressions scale score (CGI) (k=14). Patient-reported sleep quality based on measures of RLS sleep scale scores were reported in nine studies though different scales were used across studies. Our primary outcome (IRLS responders defined having ≥ 50% reduction in IRLS scale scores, Table 7) was reported in only six studies, none of which assessed ropinirole.

Table 5. Study duration and baseline characteristics of patients (means and range) in placebo-controlled studies of dopamine agonists.

Table 5

Study duration and baseline characteristics of patients (means and range) in placebo-controlled studies of dopamine agonists.

Table 6. Overall strength of evidence for individual outcomes in placebo-controlled studies of dopamine agonists.

Table 6

Overall strength of evidence for individual outcomes in placebo-controlled studies of dopamine agonists.

Table 7. Responders to treatment, International Restless Legs Syndrome Study Group Rating Scale responders (≥50% score reduction): Absolute effect per 100 patients.

Table 7

Responders to treatment, International Restless Legs Syndrome Study Group Rating Scale responders (≥50% score reduction): Absolute effect per 100 patients.

IRLS Responders (≥50% Score Reduction)

(Table 7)

Seven trials (three pramipexole trials, n=1007,28,32,37 and four rotigotine trials, n=113925,31,34,39) reported the percentage of patients who responded to treatment based on ≥50 percent reduction in IRLS symptom scale score from baseline.(Figure 3). Compared to placebo, the percentage of patients with a favorable treatment response was greater with the dopamine agonists, pramipexole and rotigotine (risk ratio [RR]=1.60; [95% confidence interval {CI}, 1.38 to 1.86]). The absolute effect in terms of responders per 100 patients was 24 more (95% CI, 15 more to 35 more) in the dopamine agonist treatment group than with placebo (high strength evidence). Results suggested some effect heterogeneity between drugs (I2=53.1%, p=0.14), with a larger effect seen in studies involving rotigotine (RR=1.76; [95% CI, 1.47 to 2.10], 25 more responders per 100 patients) than in studies of pramipexole (RR=1.46; [95% CI, 1.22 to 1.74], 21 more per 100) (Table 6). We observed a large placebo response with 25 percent to 57 percent of patients randomized to placebo having a ≥50 percent reduction in IRLS scale scores compared to placebo.

Figure 3 is a forest plot displaying results of metaanalysis of 6 placebo controlled trials of dopamine agonists (pramipexole (3 trials), rotigotine (3 trials)) for the outcome of : proportion of study participants who reported greater than 50% reduction in mean IRLS score from baseline. Results of the analysis are described in the report text.

Figure 3

Efficacy outcomes for treatment with dopamine agonists: proportion of study participants who reported greater than 50 percent reduction in mean IRLS score from baseline. CI = confidence interval; DA = dopamine agonist; M-H = Mantel Haenszel (statistical (more...)

We did not find clear evidence of a dose response based on three studies of rotigotine that assessed the effect of different doses on IRLS responders.(Appendix F) Doses ranged from 0.5 mg per day to 4.0 mg per day. In the study by Hening,25 risk ratios increased from 1.28 to 1.79 versus placebo for doses of 0.5 mg to 3.0 mg per day, but 95% confidence intervals were wide and overlapped across doses used. The results versus placebo were statistically significant for all doses except the 0.5 mg per day dose (RR=1.28; [95% CI, 0.92 to 1.78]). The study by Oertel39 evaluated five doses, ranging from 0.5 mg to 4.0 mg per day. The results versus placebo were statistically significant for the 2.0 and 3.0 mg per day doses but 95% confidence intervals were also wide and overlapped across doses used. The largest effect was seen in the 3.0 mg per day dose (RR=1.66; [95% CI, 1.16 to 2.37]). The study by Trenkwalder34 examined doses of 1.0, 2.0 and 3.0 mg/day. The effects were large and statistically significant at all studied doses. Risk ratios versus placebo ranged from 2.04 for the 1.0 mg/day dose to 2.18 for the 3.0 mg/day dose.

Responders on Clinician and Patient-Assessed Global Impressions Scale

(Figures 4 and 5, Table 8)

Figure 4 is a forest plot displaying results of metaanalysis of 13 placebo controlled trials of dopamine agonists (pramipexole (5 trials), ropinirole (5 trials), rotigotine(3 trials)) for the outcome of : proportion of study participants who reported improved or much improved on clinician rated global impressions scale. Results of the analysis are described in the report text.

Figure 4

Efficacy outcomes for treatment with dopamine agonists: proportion of study participants who reported improved or much improved on clinician-rated global impressions scale (CGI). CI = confidence interval; DA = dopamine agonist; M-H = Mantel Haenszel (statistical (more...)

Figure 5 is a forest plot displaying results of metaanalysis of 6 placebo controlled trials of dopamine agonists (pramipexole (5 trials), ropinirole (1 trials)) for the outcome of : proportion of study participants who reported improved or much improved on patient rated global impressions scale. Results of the analysis are described in the report text.

Figure 5

Efficacy outcomes for treatment with dopamine agonists: proportion of study participants who reported improved or much improved on patient-rated global impressions scale (PGI). CI = confidence interval; DA = dopamine agonist; M-H = Mantel Haenszel (statistical (more...)

Table 8. Responders to treatment, Clinician-rated global impressions (CGI) responders: participants who reported improved or much improved: absolute effect per 100 patients.

Table 8

Responders to treatment, Clinician-rated global impressions (CGI) responders: participants who reported improved or much improved: absolute effect per 100 patients.

The proportion of responders (with a rating of “much improved” or “very much improved”) on clinician and patient-reported global scales was higher for dopamine agonists than for placebo (respective risk ratios 1.45; [95% CI, 1.36 to 1.55] (k=15, n=4446) and 1.66; [95% CI, 1.45 to 1.90] (k=6, n=2069). The overall strength of evidence for both of these outcomes was high. We found borderline evidence of between-drug differences for clinician-rated global impressions (CGI) outcomes (I2=51.5%, p=0.13), but not patient-assessed global impressions (PGI) outcomes (I2=6.5%, p=0.30). Trials of pramipexole (k=5) demonstrated slightly larger effects on clinician-assessed global impressions scores (RR=1.61; [95% CI, 1.40 to 1.86]) than studies of either ropinirole (k=6) or rotigotine (k=4).

IRLS-Mean Change From Baseline

(Figure 6)

Figure 6 is a forest plot displaying results of metaanalysis of 12 placebo controlled trials of dopamine agonists (pramipexole (5 trials), ropinirole (4 trials), rotigotine(3 trials)) for the outcome of : mean change in IRLS scale score from baseline. Results of the analysis are described in the report text.

Figure 6

Efficacy outcomes for treatment with dopamine agonists: mean change in IRLS rating scale score from baseline. CI = confidence interval; DA = dopamine agonist; IRLS = International Restless Legs Syndrome Study Group; IV = Inverse variance (statistical (more...)

Treatment with dopamine agonists resulted in a small reduction in symptom severity and impact compared to placebo based on change in IRLS scale scores; the weighted mean difference (WMD) in pooled IRLS score between treatment and placebo was −4.48; (95% CI, −5.36 to −3.60) (k=13, n=3578). We found near evidence of effect heterogeneity between drugs (I2=62%, p=0.07). The magnitude of reduction in IRLS scale scores was slightly greater in studies of rotigotine25,31,34,39 (−6.07; [95% CI, −8.33 to −3.81]) (k=4, n=1286) than in studies of pramipexole24,26,28,32,37 (−4.76; [95% CI, −6.24 to −3.28]) (k=5, n=1587) or ropinirole23,27,35 (−3.49; [95% CI, −4.44 to −2.54]) (k=5, n=1517). We found no clear evidence of a dose effect in the three fixed-dose studies (1 study of pramipexole and 2 of rotigotine) that used different doses in separate arms 25,34,37 (Appendix F) Doses of pramipexole ranged from 0.25 mg/day to 0.75 mg/day. In the two studies of rotigotine, doses ranged from 0.5 mg/day to 3.0 mg/day. While mean differences in IRLS scale scores increased slightly with higher doses, the absolute effect was less than four points and the confidence intervals around the estimates for doses overlapped. The overall strength of evidence was high.

RLS Remitters

(Appendix F)

Four studies reported on the number of individuals in whom RLS symptoms completely resolved (remitters).22,25,31,34 Rotigotine increased the percentage of individuals who had remission of RLS compared to placebo based on an IRLS score of zero at the conclusion of the trial (RR=2.24; [95% CI, 1.49 to 3.35).25,31,34 In a crossover study of ropinirole (n=44), eight of 22 (26.4%) individuals had remission on ropinirole versus no individuals receiving placebo.22

RLS Quality of Life

(Figure 7)

Figure 7 is a forest plot displaying results of metaanalysis of 7 placebo controlled trials of dopamine agonists (pramipexole (3 trials), ropinirole (1 trial), rotigotine (3 trials) for the outcome of : change in RLS specific quality of life. Results of the analysis are described in the report text.

Figure 7

Efficacy outcomes for treatment with dopamine agonists: change in RLS-specific quality of life. CI = confidence interval; DA = dopamine agonist; IV = Inverse variance (statistical method); SD = standard deviation; Std = standardized

Dopamine agonist improved RLS specific quality of life as measured by standardized mean differences in RLS quality of life scale scores (k=9, n=2140). The effect size is considered small to medium in magnitude (standard mean difference (SMD)= −0.37; [95% CI, −0.48 to −0.27]). Results were similar across studies of pramipexole (k=2), ropinirole (k=2) and rotigotine (k=4), and the I2 for drug subgroup heterogeneity=0 percent. The overall strength of evidence was high.

Patient-Reported Sleep Quality

(Figure 8)

Figure 8 is a forest plot displaying results of metaanalysis of 8 placebo controlled trials of dopamine agonists (pramipexole (1 trials), ropinirole (4 trial), rotigotine (3 trials) for the outcome of : change in sleep scores assessed using Medical Outcomes Study (MOS) sleep scale. Results of the analysis are described in the report text.

Figure 8

Efficacy outcomes for treatment with dopamine agonists: change in sleep (MOS) scores. CI = confidence interval; DA = dopamine agonist; IV= Inverse variance (statistical method); SD = standard deviation; Std = standardized

Dopamine agonists improved patient-reported sleep quality compared to placebo as measured by the Medical Outcomes Study Sleep Problem Index scale (k=8) (standardized mean effect size=0.38; [95% CI, 0.29 to 0.46]. The magnitude of effect was considered small to moderate and strength of evidence was high. We found no evidence of subgroup heterogeneity between studies of pramipexole (k=1), ropinirole (k =3) or rotigotine (k=3).

Alpha-2-Delta Ligands

Efficacy of anticonvulsant drugs was evaluated in seven randomized, double-blind, placebo-controlled studies (n=1066)4045 (Tables 9 and 10). All studies involved alpha-2-delta ligands (prodrug gabapentin enacarbil, four trials; pregabalin, two trials, or gabapentin, one trial). Trials were short (one crossover trial of two 4-week intervals,46 three 6-week trials,4345 and three 12-week trials.4042 The mean age of study participants was 51 years. Women constituted 61 percent (range of means 59 to 66) of all participants randomized In the four studies that reported race,40,4446 study participants were predominantly white All participants had primary RLS. Mean symptom severity at baseline was severe (mean IRLS scale score=24). Mean RLS duration was 12 years. All trials reported change in RLS symptom severity and impact as assessed by IRLS scale score (mean change from baseline) and CGI score. Two studies used dose titration (pregabalin beginning at 150 mg/day and titrating to 450 mg/day; gabapentin 600 to 2400 mg/day based on symptom response). A randomized trial by Lee40 used fixed doses of 600 and 1200 mg/day of gabapentin enacarbil and two trials used a fixed dose of 1200 mg/day of gabapentin enacarbil.45,46 One maintenance trial had an initial 24-week single-blind period where all patients received gabapentin enacarbil, which was titrated up to 1200 mg.41 Individuals (n=194) who at week 24 showed a response to treatment, defined as an IRLS score <15 that had decreased by ≥6 points compared to baseline and were rated “much improved” or “very much improved” on the CGI, were then randomized to continuing gabapentin enacarbil 1200 mg or placebo in a 12-week double-blind phase. A multi-arm trial of pregabalin versus placebo by Allen42 assessed five different fixed doses that ranged from 50 mg per day to 450 mg per day.

Table 9. Summary of study baseline characteristics for alpha-2-delta ligand drugs trials.

Table 9

Summary of study baseline characteristics for alpha-2-delta ligand drugs trials.

Table 10. Overall strength of evidence for individual outcomes in placebo-controlled studies of alpha-2-delta ligands.

Table 10

Overall strength of evidence for individual outcomes in placebo-controlled studies of alpha-2-delta ligands.

IRLS Responders (≥50% Score Reduction)

(Figure 9)

Figure 9 is a forest plot that shows results of analysis of alpha-2-delta ligands for the outcome of: IRLS responders (defined as those with greater than or equal to 50% reduction in IRLS scale scores from baseline. Results of the analysis are described in the report text.

Figure 9

Efficacy outcomes for treatment with alpha-2-delta ligands: IRLS responders (≥50% scale score reduction). A-2-DL = Alpha-2-delta ligands; CI = confidence interval; IRLS = International Restless Legs Syndrome Study Group Rating Scale; M-H = Mantel (more...)

Three trials40,42,44 (low risk of bias) evaluated IRLS responders. Alpha-2-delta ligands compared to placebo significantly increased the percentage of IRLS responders (RR=1.66; [95% CI, 1.33 to 2.09]).40,42,44 The absolute effect in terms of responders per 100 patients was 25 more (95% CI, 12 more to 41 more). The strength of evidence was high. There was no clear evidence of dose effect based on IRLS responders or IRLS total scores in the studies by Lee40 or Allen.42 In the trial by Allen, a total of 137 subjects were enrolled across study arms and doses. While effect sizes increased with higher doses, confidence intervals were wide and overlapped across doses.

Responders on Clinician and Patient-Assessed Global Impressions Scale

(Figure 10)

Figure 10 is a forest plot that shows pooled results from 2 placebo controlled trials of the anticonvulsant drugs pregabalin (1 trial) and gabapentin (1 trial) for the outcome of: proportion of study participants who reported improved or much improved on clinician rated global impressions scale. Results of the analysis are described in the report text.

Figure 10

Efficacy outcomes for treatment with alpha-2-delta ligands: proportion of patients who reported improved or much improved on the clinician-rated global impressions scale (CGI). A-2-DL = Alpha-2-delta ligands; CI = confidence interval; M-H = Mantel Haenszel (more...)

The proportion of patients who reported improved or very much improved on the CGI was significantly greater for the alpha-2-delta ligand group though there was evidence of heterogeneity between treatment subgroups (RR=1.60 [95% CI, 1.21 to 2.10]). Improvement was significant for gabapentin enacarbil therapy but not for pregabalin treatment (p=0.03 for interaction). In the crossover trial (not pooled) by Winkelman 74 percent of patients treated with gabapentin enacarbil were considered much improved or very much improved on the CGI compared to 36 percent of patients treated with placebo (p<0.001).46

IRLS-Mean Change From Baseline

(Figure 11, Appendix F)

Figure 11 is a forest plot that shows pooled results from 2 placebo controlled trials of the anticonvulsant drugs pregabalin (1 trial) and gabapentin (1 trial) for the outcome: mean change in IRLS scale score from baseline. Results of the analysis are described in the report text.

Figure 11

Efficacy outcomes for treatment with alpha-2-delta ligands: mean change in IRLS scale score from baseline. A-2-DL = Alpha-2-delta ligands; CI = confidence interval; IRLS = International Restless Legs Syndrome Study Group Rating Scale; IV = Inverse variance (more...)

Gabapentin enacarbil40,43,45 (k=2), pregabalin 42,44(k=2), and gabapentin (ref 33) reduced symptom severity compared to placebo. The pooled weighted mean change in IRLS score from baseline between alpha-2-delta ligands and placebo groups was −4.26; [95% CI, −5.75 to −2.77] (k=3). (WMD= −4.26; [95% CI, −5.75 to −2.77]). The crossover trial (not pooled) by Winkelman also found mean change in IRLS score from baseline significantly favored gabapentin enacarbil.46 The mean treatment difference versus placebo was −6.6 points [95% CI, −8.6 to −4.6]. Strength of evidence was high. We identified no heterogeneity between studies. Similar effects were seen in two other studies (one each of pregabalin and gabapentin) that reported end-of-study IRLS results (WMD = −6.56; [95% CI, −9.27 to −3.86]). There was some evidence of heterogeneity between studies, with the effect of pregabalin versus placebo (WMD= −4.35) being less than that in the crossover study of gabapentin (WMD= −8.30), I2=53.0%, p=0.14). The strength of evidence was moderate. In a maintenance trial, patients continuing gabapentin enacarbil therapy were significantly less likely to experience relapse (defined as an increase by ≥6 points from randomization to a IRLS score ≥15 points and a rating of “much worse” or “very much worse” on the CGI) than patients allocated to placebo, 9 percent and 23 percent, respectively (RR=0.41; [95% CI, 0.20 to 0.85]).41

RLS Remitters

One multi-arm gabapentin enacarbil trial (n=325) reported the number of patients who achieved an IRLS score of zero points.40 The percentages of remitters in the 600 and 1200 mg dose groups were 26 and 23 percent, respectively, compared to 12 percent in the placebo group. After pooling the two dose groups, the RR was 2.13 [95% CI, 1.17 to 3.89]. One pregabalin trial reported the number of patients who achieved an IRLS score of zero points (Garcia-Borreguero 2010 ref). There were nine remitters (30%) in the pregabalin group compared with four (14%) in the placebo group, a difference that was not statistically significant (RR=2.10; [95% CI, 0.73 to 6.06]).

RLS Relapse

Fewer patients maintained on gabapentin enacarbil compared to placebo experienced RLS relapse. Nine percent of patients randomized to gabapentin enacarbil experienced relapse, defined as an increase by ≥6 points from randomization to a IRLS score ≥15 points and a rating of “much worse” or “very much worse” on the CGI, compared to 23 percent of the placebo patients (RR=0.41; [95% CI, 0.20 to 0.85]).41 Mean change from randomization in IRLS scores were also significantly smaller in the gabapentin enacarbil group (1.9 points) compared to placebo (3.9 points). The mean difference was −2.00 points [95% CI −3.91 to −0.09].

RLS Quality of Life

Two trials showed mixed results on quality of life measures (SMD=0.27 [95% CI, −0.17 to 0.70]) (low strength of evidence). 42,45 One fixed-dose study of pregabalin found no statistically significant improvement in the Johns Hopkins Restless Legs Syndrome Quality of Life questionnaire (RLS-QoL) with any dose versus placebo over a 6-week period (k=1, n=122).42 The strength of evidence was low. Gabapentin enacarbil improved RLS-QoL scores at week 12 compared with placebo (mean [SD] change from baseline: gabapentin enacarbil, 21.4 [17.00]; placebo, 14.1 [17.32]; RLS treatment difference 7.8; P < 0.0001) (SMD=0.42 [95% CI, 0.16 to 0.69]).45 The strength of evidence was moderate.

Patient-Reported Sleep Quality

All four studies provided information on self-rated sleep. All demonstrated a statistically significant improvement due to alpha-2-delta ligands versus placebo. However, variation in scales used and reporting methods precluded pooling all studies, and in some cases, precluded identifying the magnitude of effect. Four studies used the Medical Outcomes Scale, either the full nine-item Medical Outcome Study sleep problem indexes I or II (MOS-SPI-I or II scale) or MOS-sleep adequacy,40,4345,83 In two trials,40,45 treatment with gabapentin enacarbil significantly improved sleep adequacy based on the pooled MOS-sleep adequacy domain (SMD=0.53; [95% CI, 0.33 to 0.72], k=2). The magnitude of effect was considered moderate and strength of evidence was high. Self-rated daytime sleepiness using the Epworth Sleepiness Scale was not significantly different in one study reporting this outcome.45

Long-Term Tolerability and Durability

Long-Term Durability and Sustainability

Data from 18 observational studies and open label extensions of RCTs indicated that pharmacological treatment durability and sustainability, as measured by withdrawal from treatment and reasons for withdrawal, was fair to poor (Table 11). Studies reported on gabapentin, “multiple opioids,” methadone, levodopa, and the dopamine agonists pramipexole, ropinirole, and rotigotine. Withdrawals and reasons for withdrawals varied widely across examined drugs and durations. Study design, participant and RLS characteristics, and methods for ascertaining withdrawals and reasons for withdrawal varied. Withdrawal from treatment at 1 year or more ranged from 13 to 57 percent. Withdrawal due to lack of efficacy occurred in 6 to 32 percent.

Table 11. Long-term harms with pharmacologic treatment: augmentation.

Table 11

Long-term harms with pharmacologic treatment: augmentation.

Miscellaneous Pharmacological and Nonpharmacological Therapies

Two miscellaneous pharmacological studies and four small, short-term studies assessed nonpharmacological therapies in adults with moderate to severe RLS (Tables 12 and 13, Appendix E, and Appendix F). One small good quality short-term RCT (n=46)15 found intravenous iron (ferric carboxymaltose) significantly improved IRLS symptom scale scores compared to placebo over 28 days of therapy. Mean improvements for iron and placebo were reductions of 8.9 and 4.0 points, respectively, with a mean difference of −4.90 [95% −9.27 to −0.53]. The strength of evidence was moderate. There were also significantly greater improvements in CGI, RLS-QoL, and sleep measures (MOS total score) versus placebo.

Table 12. Strength of evidence for the miscellaneous pharmacologic trials.

Table 12

Strength of evidence for the miscellaneous pharmacologic trials.

Table 13. Strength of evidence for the nonpharmacologic trials.

Table 13

Strength of evidence for the nonpharmacologic trials.

One small good quality RCT47 evaluated the antidepressant bupropion. Mean change in IRLS symptom scores after 6 weeks compared to baseline were 10.4 points lower with bupropion compared 7.6 points lower with placebo, a non statistically significant difference (p=0.11). Strength of evidence was considered low.

A good quality RCT18 of pneumatic compression devices worn for at least 1 hour each day for 4 weeks starting prior to the time when symptoms typically began found better end-of-study (4 weeks) IRLS symptom scale scores (8.4 +/− 3.4 versus 14.1 +/− 3.9; p=0.006), dimensions of the RLS quality of life instrument (P<0.05 for all four dimensions), and daytime somnolence measures as assessed by the Epworth Sleepiness Scale (6.5 +/− 4.0 vs. 10.6 +/− 3.8; p=0.04) and complete resolution of symptoms (8 [38.1%] vs. 0 [0%]; p=0.007) more than sham devices (moderate quality of evidence). Enrollees had moderately severe RLS (mean baseline IRLS score=19.6) that was on average 4 years in duration. Nearly two thirds of subjects were taking current medications for RLS (mostly pramipexole, ropinirole, or iron). Pneumatic compression devices were programmed to inflate the leg wraps for 5 seconds every minute. The only difference between intervention and sham devices was that the therapeutic devices generated 40 cm H2O of air pressure with each inflation cycle, while sham devices generated a 3 to 4 cm H2O rise in pressure. No subjects initiated new medical therapy for RLS or increased RLS medications during the study. None of the patients using placebo devices decreased or discontinued medical therapy, while five (23.3) individuals using therapeutic devices decreased or discontinued medical therapy. It is possible that blinding was inadequate as patients could have detected differences in compression due to air pressure from the intervention versus the sham devices.

One low quality RCT21 of 34 patients evaluated near-infrared light treatment compared to sham treatment. Twelve 30-minute near-infrared light treatment sessions were applied over four weeks. Near-infrared light treatment significantly improved IRLS symptom scores more than sham, −13.4 points versus −4.5 points, respectively, with a MD of −9.00 [95% CI= −13.21 to −4.79].21 However, the trial has questionable internal validity as they used an odd/even method of randomization resulting in a low strength of evidence. In one fair quality study, treadmill walking and lower body resistance exercise performed three times weekly for 12 weeks improved IRLS scale scores (WMD= −9.4 [95% CI, −13.9 to −4.9]) compared with usual care (low quality of evidence). However, the authors reported results for only for 28 completers from 41 subjects enrolled.

A fair quality RCT of the botanical preparation valerian at 800 mg daily for 8 weeks did not improve IRLS symptom scale scores (p=0.69), Pittsburgh Sleep Quality Index scores (p=0.94) or Epworth Sleepiness Scale scores (0.64) more than placebo among 48 adults with severe RLS symptoms (mean IRLS scores=23.5) occurring at least three times per week (low quality of evidence).

Comparative Effectiveness of RLS Treatments and Dose Response

We describe two studies that directly compared two active interventions. We also report whether effectiveness or harms varies by drug dose. We described above subgroup findings of effectiveness and harms across pharmacologic interventions from placebo controlled trials by assessing whether there was evidence of statistically significant heterogeneity. However, we urge caution for drawing conclusions about comparative effectiveness and harms based on these indirect subgroup comparisons.

One small crossover trial (n=39)16 compared dopamine agonist pramipexole treatment to dual release levodopa/benserazide therapy over two periods of four weeks in patients not previously diagnosed or treated. Improvement of IRLS scores from baseline trended toward significance with pramipexole treatment, with a mean reduction of 7.2 points compared to 4.0 points for dual therapy (p=0.054). For patients with severe RLS (38%, denoted by an IRLS baseline score >20), there was a significant mean reduction in IRLS scores with pramipexole versus levodopa/benserazide, −8.5 versus −4.3 points, respectively (p=0.047). The quality of evidence was low.

One 30-week study17 (n=361) found that the dopamine agonist cabergoline improved IRLS symptom scale scores (WMD= −6.80; [95% CI, −9.02 to −4.58]) and RLS quality of life more than Levodopa (WMD= −7.10; [95% CI, −9.94 to −4.26]) in white adults with severe RLS (IRLS scale score=25.7) (Appendixes C and D). The quality of evidence was moderate.

We assessed whether the effects of dopamine agonists varied by dose based on reported outcomes from multiarmed fixed-dose trials. Most trials used dose titration at the discretion of the clinician based on symptom response and adverse effects, and did not report the mean or median doses used or outcomes according to dose. As previously noted (in the section describing specific outcomes), we found no clear evidence of a dose effect for the outcomes of IRLS responders or mean change in IRLS scale scores for either dopamine agonists or GABA agonists.

For dopamine agonist and the outcome of IRLS responders, three studies of rotigotine assessed the effect of doses ranging from 0.5 mg per day to 3.0 mg per day (Appendix F). In the study by Hening,25 risk ratios increased from 1.28 to 1.79 versus placebo for doses of 0.5 mg to 3.0 mg per day, but 95% confidence intervals were wide and overlapped across doses used. Results versus placebo were statistically significant for all doses except the 0.5 mg per day dose (RR=1.28; [95% CI, 0.92 to 1.78]). The study by Oertel39 evaluated five doses, ranging from 0.5 mg to 4.0 mg per day. The results versus placebo were statistically significant for the 2.0 and 3.0 mg per day doses but 95% confidence intervals were also wide and overlapped across doses used. The largest effect was seen in the 3.0 mg per day dose (RR=1.66; [95% CI, 1.16 to 2.37]). The study by Trenkwalder34 examined doses of 1.0, 2.0 and 3.0 mg/day. The effects were large and statistically significant at all studied doses. Risk ratios versus placebo ranged from 2.04 for the 1.0 mg/day dose to 2.18 for the 3.0 mg/day dose.

Three fixed-dose studies (one study of pramipexole and two of rotigotine) used different doses in separate arms and reported the proportion of IRLS scale scores at different doses of dopamine agonists. Doses of pramipexole ranged from 0.25 mg/day to 0.75 mg/day. In the two studies of rotigotine, doses ranged from 0.5 mg/day to 3.0 mg/day. While mean differences in IRLS scale scores increased slightly with higher doses, the absolute effect was less than 4 points and the confidence intervals around the estimates for doses overlapped (Appendix F).

For alpha-2-delta ligands, we found no clear evidence of dose effect based on IRLS responders or IRLS total scores in the study by Allen42 evaluating pregabalin. A total of 208 subjects were enrolled across study arms and doses. Doses of pregabalin ranged from 50 to 450 mg/day. While effect sizes increased with higher doses, confidence intervals were wide and overlapped across doses (Appendix F).

Key Question 2. What are the harms from RLS treatments?

  1. What are the harms from RLS treatments when compared with placebo or no treatment?
  2. What are the harms from RLS treatments when compared with other active treatments?
  3. What are the long-term harms from treatment?

Key Points

  • Study withdrawals due to adverse effects were more common with dopamine agonist treatment than with placebo (moderate-strength evidence). Differences between treatments were primarily due to an increase in withdrawals related to adverse effects (application site reactions) reported in three trials of transdermal rotigotine
  • Study withdrawals (due to any reason) from RCTs were slightly less common with dopamine agonist treatments than with placebo (moderate-strength evidence)
  • More patients randomized to dopamine agonist had at least one adverse effect compared to placebo (high-strength evidence)
  • Short-term adverse effects from treatment with dopamine agonists compared to placebo were nausea, vomiting, somnolence, and fatigue (high-strength evidence for all these outcomes)
  • Application site reactions were much more common with transdermal rotigotine than with placebo (high-strength evidence)
  • Study withdrawals (due to any reason) were less common in patients randomized to alpha-2-delta ligands than to placebo (high-strength evidence)
  • Somnolence, unsteadiness or dizziness, and dry mouth were much more common with alpha-2-delta ligands than with placebo (high-strength evidence for all these outcomes)
  • Incidences of diarrhea and blood phosphorus decrease were reported with intravenous iron therapy.
  • No adverse events, except a few cases of nausea, were reported in the trial evaluating bupropion
  • One small crossover trial reported higher incidences of augmentation and rebound (RLS symptoms in the early morning) with dual release levodopa/benserazide therapy versus pramipexole
  • Data from observation studies indicates that long-term augmentation ranged from 2.5 percent to 60 percent and varied markedly by type of dopamine agonist, followup time, study design, and method used to ascertain augmentation. We found no clear pattern to explain this variability
  • Withdrawal from mostly dopamine agonist and levodopa treatment was common, occurring in 13 percent to 57 percent of subjects due either to lack of efficacy or adverse effects. Most studies reported treatment withdrawals greater than 20 percent at 1 year

Short-Term Harms

We evaluated three measures of short-term treatment harms from randomized controlled trials: any study withdrawal, (Figures 1215) study withdrawal due to adverse effects, and percentage of patients reporting at least one adverse effect (Appendix G) (Figures 1617). Patients were less likely to withdraw from dopamine agonist treatment than from placebo treatment (20% vs. 24%; RR=0.79; [95% CI, 0.66 to 0.94], k=16) (moderate strength of evidence). Study withdrawals due to adverse effects were more common with dopamine agonist treatment (10% vs. 6%; RR=1.37; [95% CI, 1.03 to 1.82], k=16) (high strength of evidence). More patients experienced at least one adverse effect with dopamine agonist than with placebo (RR=1.19; [95% CI, 1.12 to 1.28], k=16) (high strength of evidence) (Figure 16). Results did not significantly vary compared to placebo in studies of pramipexole, ropinirole or rotigotine. We also assessed specific short-term adverse effects (Appendix G).

Figure 12 is a forest plot displaying results of metaanalysis of 14 placebo controlled trials of dopamine agonists (pramipexole (5 trials), ropinirole (6 trials), rotigotine(3 trials)) for the outcome of: any study withdrawal. Results of the analysis are described in the report text.

Figure 12

Short-term harms of treatment with dopamine agonists: any study withdrawal. CI = confidence interval; DA = dopamine agonist; M-H = Mantel Haenszel (statistical method)

Figure 13 is a forest plot displaying results of metaanalysis of 14 placebo controlled trials of dopamine agonists (pramipexole (5 trials), ropinirole (6 trials), rotigotine(3 trials)) for the outcome of : study withdrawals due to adverse events. Results of the analysis are described in the report text.

Figure 13

Short-term harms of treatment with dopamine agonists: study withdrawals due to adverse events. CI = confidence interval; DA = dopamine agonist; M-H = Mantel Haenszel (statistical method)

Figure 14 is a forest plot displaying results of analysis of alpha-2-delta ligands for the outcome of : any study withdrawals. Results of the analysis are described in the report text.

Figure 14

Short-term harms of treatment with alpha-2-delta ligands: any study withdrawals. A-2-DL = Alpha-2-delta ligands; CI = confidence interval; M-H = Mantel Haenszel (statistical method)

Figure 15 is a forest plot displaying results of analysis of alpha-2-delta ligands for the outcome of : study withdrawals due to Adverse Events. Results of the analysis are described in the report text.

Figure 15

Short-term harms of treatment with alpha-2-delta ligands: study withdrawals due to adverse events. A-2-DL = Alpha-2-delta ligands; CI = confidence interval; M-H = Mantel Haenszel (statistical method)

Figure 16 is a forest plot displaying results of metaanalysis of 14 placebo controlled trials of dopamine agonists (pramipexole (5 trials), ropinirole (6 trials), rotigotine(3 trials)) for the outcome of : patients with greater than or equal to 1 adverse event. Results of the analysis are described in the report text.

Figure 16

Patients with ≥1 adverse effect, dopamine agonist trials. CI = confidence interval; DA = dopamine agonist; M-H = Mantel Haenszel (statistical method)

Figure 17 is a forest plot displaying results of analysis of alpha-2-delta ligands for the outcome of : patients with greater than or equal to 1 adverse event. Results of the analysis are described in the report text.

Figure 17

Patients with ≥1 adverse effect, alpha-2-delta ligands trials. A-2-DL = Alpha-2-delta ligands; CI = confidence interval; M-H = Mantel Haenszel (statistical method)

We observed more short-term adverse effects with dopamine agonists than with placebo, as follows: nausea (23% vs. 7%, RR=3.31 [95% CI, 2.53 to 4.33], k=15), vomiting (7% vs. 2%, RR=4.48 [95% CI, 2.68 to 7.48], k=8), and somnolence (12% vs. 6%, RR=2.04; [95% CI, 1.50 to 2.76], k=8). (overall high strength evidence for these outcomes). These adverse effects occurred in across of the evaluated dopamine agonists though magnitude of effect varied slightly by type of dopamine agonist. Application site reactions were much more common with transdermal rotigotine than with placebo, 29 versus 3 percent, respectively (RR=8.32; [95% CI, 3.45 to 20.05], k=4) (high strength of evidence). The frequencies of reactions were generally greater with increasing doses although not significantly.

There was an overall nonsignificant increase in study withdrawals due to adverse effects associated with alpha-2-delta ligand treatment compared with placebo (8% vs. 4%; RR=1.86; [95% CI, 0.95 to 3.63], k=4) (moderate strength of evidence). Patients allocated to alpha-2-delta ligand therapy were less likely to withdraw from treatment due to any reason than patients allocated to placebo (12% vs. 18%; RR=0.68; [95% CI, 0.47 to 0.98], k=4) (high strength of evidence).

Short-term adverse effects that were significantly greater with alpha-2-delta ligand treatment compared to placebo were somnolence (19% vs. 3%, RR=5.37; [95% CI, 2.38 to 12.12], k=5), unsteadiness or dizziness (17% vs. 4%, RR=4.11; [95% CI, 2.19 to 7.71], k=4), and dry mouth (6% vs. 1%; RR=3.31; [95% CI, 1.09 to 10.05], k=4) (overall strength of evidence was high for these outcomes).

Three subjects each reported diarrhea (12.5%) and blood phosphorus decrease (12.5%) with intravenous iron therapy.15 No subjects in the placebo arm reported these events. Two patients allocated to bupropion and one to placebo discontinued treatment due to nausea.47 No other adverse events were reported.

Comparative Harms

One small moderate quality crossover trial (n=39)16 of two four-week periods reported higher incidences of augmentation and rebound (RLS symptoms in the early morning) with dual-release levodopa/benserazide therapy versus pramipexole treatment in de novo patients (Appendix G). A higher incidence of nausea, headache, and vomiting was associated with pramipexole.

One good quality 30-week randomized trial reported that compared to levodopa, cabergoline resulted in less augmentation and less augmentation leading to withdrawal (Appendix G). The drugs did not differ with regard to “any study withdrawals.” Cabergoline is not approved for treatment of RLS and is rarely used in the United States due in part to FDA warnings about increased risk of cardiac valvular abnormalities.

We observed some subgroup differences across types of dopamine agonist in certain adverse events (Appendixes D and E). We caution about making direct comparisons, however, because these are based on subgroup differences observed in placebo-controlled trials, not direct comparisons between drugs. Study and patient characteristics may account for some or all of the between-study differences or lack of differences that we observed. Withdrawals due to site application reaction were unique to transdermal rotigotine; all other studied pharmacological agents are taken orally. The increase in site application reaction was the main factor leading to a greater number of study withdrawals in studies of rotigotine compared to studies of pramipexole or ropinirole (I2=74%, p=0.02). Compared to placebo, fatigue was more common in the single study of ropinirole that reported this outcome than in studies of pramipexole (k=4) or rotigotine (k=2) (I2=92.6%, p<0.00001).

We assessed whether harms varied according to different drug doses based on findings from fixed-dose studies that assessed different doses (Appendix F). Compared to placebo, the relative risk of site reaction (k=3) was similar across doses of rotigotine, ranging from 0.5 to 3.0 mg/day. The risk ratios of nausea, fatigue, and somnolence for rotigotine, pramipexole, and ropinirole versus placebo also did not vary significantly by dose, but the numbers of patients and events in each dose subgroup were small, and confidence intervals were wide and overlapped.

Long-Term Harms and Withdrawal From Treatment

We used data from 18 observational studies including open-label extensions of RCTS that reported at least 6 months of followup to assess the percentage individuals withdrawing from pharmacological treatments and reasons for withdrawal (lack of efficacy, adverse events, augmentation, other) (Table 11). Followup duration ranged from 6 months to 10 years. Data were available for gabapentin (one study), opioids (multiple opioids, one study, methadone, one study), and dopamine agonists. Withdrawal from treatment was common, occurring in 13 percent to 57 percent of subjects. The highest withdrawals were in studies of levodopa (withdrawals all greater than 40%). Withdrawals in studies of gabapentin, and the dopamine agonist were typically greater than 20 percent. Reasons for withdrawal were adverse events (including augmentation) in about one-half of individuals, and lack of efficacy in 20 to 30 percent.

Augmentation was reported in 15 studies, all of which involved dopamine agonists or levodopa. In general, augmentation was common across dopaminergic or dopamine agonist drugs. Two small studies of levodopa reported that augmentation occurred in 35 to 60 percent of individuals at 6 to 12 months duration. Six studies of pramipexole with followup duration of 6 months to 10 years reported augmentation in 7 percent to 33 percent of individuals. Augmentation was reported in 10 and 23 percent of individuals treated with rotigotine at 1 and 5 years of followup. A single study of ropinirole with 1 year followup reported that only 2.3 percent of individuals experienced augmentation. It is not clear why period prevalence estimates varied widely across drugs or time periods.

Additional information on harms of individual drugs used for RLS treatment was obtained by searching the FDA website. We searched for: (1) any drug that has FDA approval for primary RLS treatment; (2) any drug studied in RCTs of individuals with primary RLS; (3) all drugs with long-term harms and withdrawal from treatment data from our review of 18 observational studies or longer-term extensions of RCTs in patients with primary RLS that met our eligibility criteria and were included above; (4) recommended for treatment of primary RLS in treatment algorithms (Table 10). These included drugs in the classes: dopaminergic agents, anticonvulsants (GABA-analogs), sedative-hypnotics and opioids. The FDA described adverse effects and warnings are derived from individuals using these medications that may not have RLS. Thus it is not possible to know if these adverse effects occur and to what frequency/severity among individuals with RLS.

Data from two unpublished ropinirole 52-week extension studies reported that adverse events described as “restless legs syndrome” (presumably augmentation) occurred in 9 percent (28/309) of patients in a European study (study number 101468/192) (www.gsk-clinicalstudyregister.com/result_comp_list.jsp?compound=Ropinirole) and 16 percent (13/81) of patients in an American study (study number 101468/243) (Information about both studies can be found at www.gsk-clinicalstudyregister.com/result_comp_list.jsp?compound=Ropinirole. The number of subjects withdrawing in the European study was 19 percent, 8 percent due to adverse events and 4 percent due to lack of efficacy. The respective percents in the American study (101468/243) were 26, 9, and 1 percent.

Key Question 3. What is the effect of patient characteristics (age, sex, race, comorbidities, disease severity, etiology, iron status, pregnancy, end-stage renal disease) on the benefits and harms of treatments for RLS?

Key Points

  • No RCTs examined the effect of patient or RLS characteristics on benefits and harms of treatments for primary RLS.
  • No RCTs enrolled children or women who were pregnant or recently postpartum, and nearly all specifically excluded these individuals.
  • No eligible studies enrolled individuals with end-stage renal disease, and almost all specifically excluded these individuals.
  • Two small randomized trials of iron therapy versus placebo in adults with iron deficiency provided low strength of evidence that iron may improve IRLS symptom scale scores and possibly the percentage of adults considered IRLS responders.

We found almost no evidence addressing the effect of patient characteristics on benefits and harms of treatments for RLS. While studies generally provided baseline sex, age, race, disease severity, and primary and secondary RLS etiologies, results were not stratified by these characteristics. No study evaluated patients exclusively based on sex, age, race, comorbidities, disease severity/duration, or prior treatment characteristics. On average, trials enrolled middle-aged white adults (mostly women) with primary RLS of long duration, many of whom had been treated previously, and whose symptoms were frequent and high-moderate to severe.

Studies typically excluded patients with psychiatric or other serious comorbid conditions including renal or liver disease and pregnant women or those contemplating becoming pregnant. No studies assessed treatments in pregnant women, and no eligible studies assessed treatments in patients with end-stage renal disease. The minimum age for entry to studies was always at least 18 years, thus we found no information on treatment of RLS in children or adolescents.

Two small good quality RCTs evaluated iron therapy66,67 (one intravenous and one oral) in patients with RLS secondary to iron deficiency (Table 14, Appendix E). One 12-week trial of 18 subjects found that compared to placebo, iron reduced IRLS scale scores by 9.16 points (95% CI, −15.2 to −3.1). Another trial of intravenous iron sucrose administered five times over 3 months in 60 subjects found no difference versus placebo at 12 months in mean change in IRLS scale scores (p=0.47). A post hoc analysis at 11 weeks found an increase in the percentage of subjects considered IRLS responders among those randomized to iron (RR=1.85; [95% CI, 1.07 to 3.18]). By 12 months, 21 of 31 subjects (68%) in the placebo group and nine of 29 (31%) in the iron group withdrew. Of these, 19 and five respectively withdrew due to lack of efficacy. The strength of evidence for these outcomes was low.

Table 14. Strength of evidence for iron trials for the treatment of secondary RLS.

Table 14

Strength of evidence for iron trials for the treatment of secondary RLS.

No studies assessed treatments in pregnant or recently postpartum women, and no eligible studies assessed treatments in patients with end-stage renal disease. The minimum age for entry to studies was always at least 18 years, thus we found no information on treatment of RLS in children or adolescents. Studies typically excluded patients with psychiatric or other serious comorbid conditions including renal or liver disease and pregnant women or those contemplating becoming pregnant.

Study Quality/Risk of Bias and Applicability

Nearly all of the pharmacologic trials (dopamine agonist, anticonvulsants, and iron therapies) but only one of three nonpharmacological trials were considered of good quality or having a low risk of bias. The applicability of the included evidence for RLS treatments is limited. Included studies were mostly short-term, placebo-controlled efficacy studies of dopamine agonists and alpha-2-delta ligands conducted in a highly selected population of adults with high-moderate to very severe primary RLS of long duration. Applicability to adults with less frequent or less severe (mild to moderate) RLS symptoms, children, or those with secondary RLS is unknown. Furthermore, studies did not address the comparative effectiveness and harms of commonly used treatments, or the effect of patient or RLS characteristics on outcomes.

Cover of Treatment for Restless Legs Syndrome
Treatment for Restless Legs Syndrome [Internet].
Comparative Effectiveness Reviews, No. 86.
Wilt TJ, MacDonald R, Ouellette J, et al.

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