Pharmacologic Therapy for Primary Restless Legs Syndrome a Systematic Review and Meta-Analysis

REVIEW ARTICLE

Pharmacologic Therapy for Primary Restless Legs Syndrome A Systematic Review and Meta-analysis

Timothy J. Wilt, MD, MPH; Roderick MacDonald, MS; Jeannine Ouellette; Imran S. Khawaja, MD; Indulis Rutks, BA; Mary Butler, PhD, MBA; Howard A. Fink, MD, MPH

Importance: Restless legs syndrome (RLS) is a neuro- proved patient-reported sleep scale scores and quality- logical disorder characterized by unpleasant sensations of-life measures. High-strength evidence demonstrated in the legs and a distressing, irresistible urge to move them. that calcium channel alpha-2-delta ligands increased the We conducted a systematic review to evaluate efficacy, proportion of IRLS responders compared with placebo safety, and comparative effectiveness of pharmacologic (61% vs 37%) (risk ratio, 1.66 [95% CI, 1.33-2.09]; 3 treatments for primary RLS. trials). Adverse events associated with dopamine agonists included nausea, vomiting, and somnolence. Alpha- Evidence Acquisition: We included randomized con- 2-delta ligands adverse events included somnolence and trolled trials (RCTs), published in English, reporting ef- unsteadiness or dizziness. ficacy outcomes and harms of pharmacologic treatments for primary RLS of at least 4 weeks’ duration. Conclusions and Relevance: On the basis of short- MEDLINE and other databases were searched through term RCTs that enrolled highly selected populations with June 2012. Reviewers extracted outcomes and adverse events and rated the strength of evidence. long-term high-moderate to very severe symptoms, dopamine agonists and calcium channel alpha-2-delta li- Results: We identified 29 eligible RCTs. We found high- gands reduced RLS symptoms and improved sleep out- strength evidence that the proportion of patients who had comes and disease-specific quality of life. Adverse effects a clinically important response (International Restless Legs and treatment withdrawals due to adverse effects were Syndrome [IRLS] responders), defined as a 50% or greater common. reduction from baseline in mean IRLS symptom scale scores, was greater with dopamine agonist therapy com- JAMA Intern Med. 2013;173(7):496-505. pared with placebo (61% vs 41% ) (risk ratio, 1.60 [95% Published online March 4, 2013. CI, 1.38-1.86]; 7 trials). Dopamine agonists also im- doi:10.1001/jamainternmed.2013.3733 Author Affil Chronic Dis Research (D ESTLESS LEGS SYNDROME Diagnostic criteria for RLS were estab- and Messrs M (RLS) is characterized by lished by the International Restless Legs Rutks) and D unpleasant sensations in Syndrome (IRLS) Study Group in 19953 Psychiatry ( the legs and a distressing, and revised in 2003.1 The criteria include Minneapolis irresistible urge to move the following: (1) an urge to move the legs, System, Min Minnesota; M them.R The etiology of primary RLS is un- usually accompanied by uncomfortable or Evidence-Ba known. The disorder also occurs second- unpleasant sensations in the legs; (2) un- Minneapolis ary to other conditions such as iron defi- pleasant sensations or urge to move that and Fink, M ciency, end-stage renal disease, and begin or worsen during periods of rest or and Rutks, a pregnancy.1 A family history of RLS is com- inactivity such as lying or sitting; (3) un- Department 1 Wilt and Fin mon, but genome-wide association stud- pleasant sensations or urge to move that (Dr Khawaja ies have produced inconsistent findings.2 are partly or totally relieved by move- Minnesota, M Restless leg syndrome can result in re- ment such as walking, bending, and University o duced quality of life (QoL) and have a stretching, at least as long as the activity of Public He negative impact on sleep, leading to day- continues; and (4) unpleasant sensations (Drs Wilt, B Ms Ouellette time fatigue. Effective treatment options or urge to move that are worse in the eve- Research Ed Author Affiliations are listed at are not well established, and scant evi- ning or at night than during the day or only Clinical Cen the end of this article. dence exists to guide treatment selection. occur in the evening or night. Center, Min

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 Restless leg syndrome varies in INFORMATION SOURCES mates of overall risk ratios (RRs), symptom severity and frequency. weighted mean differences (WMDs), Mild RLS may cause minor annoy- We searched the bibliographic data- or standardized mean differences ance, but severe RLS can negatively bases MEDLINE, EMBASE, and Natu- (SMDs) and the corresponding 95% affect work, social activities, func- ral Standards through June 2012 for confidence intervals. Data were pooled RCTs evaluating treatment efficacy and and analyzed in Review Manager statis- tion, and emotional well-being. Sleep tical software (RevMan version 5.1; disruption induced by RLS may lead reported adverse effects (eAppendix 1; http://www.jamainternalmed.com). To The Nordic Cochrane Centre, The to poor daytime functioning, anxi- identify completed trials and to reduce Cochrane Collaboration). We assessed ety, and depression. Sleep depriva- publication bias, we searched Coch- statistical heterogeneity between trials tion and daytime fatigue are com- rane Central, the International Con- and for subgroups of drugs using the I2 mon reasons patients with RLS seek trolled Trials Registry Platform test and observation of the direction of treatment.4 Prevalence estimates for (ICTRP), Clinicaltrials.gov, FDA web- the effect of the studies. Scores of ap- bothersome RLS in the United States sites, and the National Institutes of proximately 50% and effect sizes that range from 1.5% to 7.4% in adults.1,5 Health (NIH) RePORTer. We included did not fall on the same side of “no ef- The variation reflects different ap- eligible unidentified trials referred by fect” suggested substantial heteroge- peer reviewers. neity. Number needed to treat (NNT) proaches to diagnosing RLS and de- and number needed to harm (NNH) fining its presence and severity and DATA EXTRACTION AND were calculated for dichotomous out- the fact that many RLS question- comes. For the fixed-dose trials, we naires do not account for individu- QUALITY ASSESSMENT analyzed only doses recommended for als who have other conditions with current clinical practice if possible. We similar symptoms. Data from included studies were ab- examined funnel plots and performed Pharmacologic treatment is gen- stracted into evidence tables by 1 re- Egger intercept tests9 to detect publica- viewer (R.M.) and validated by a sec- tion bias. erally reserved for patients whose ond reviewer (T.J.W.). Our primary symptoms are frequent (several outcome was IRLS responders defined times per week) and cause moder- as patients with a 50% or greater reduc- RESULTS ate to very severe discomfort and tion in IRLS scale score from baseline. bother. Three dopamine agonists We also assessed the mean change in Our literature search for RCTs of (pramipexole, ropinirole, and roti- IRLS scale score from baseline; percent- pharmacologic treatments of pri- gotine) and 1 calcium channel alpha- age of patients with complete remis- mary RLS yielded 29 references 2-delta ligand (gabapentin enacar- sion; percentage of patients reporting meeting our inclusion criteria, bil) are currently approved by the “much improved” or “very much im- shown in Figure 1. Food and Drug Administration proved” on clinician-assessed global impression (CGI) or patient-assessed global (FDA) for treatment of moderate to impression scales; RLS QoL; patient- DOPAMINE severe RLS. reported sleep quality; number of indi- We conducted a systematic re- viduals experiencing adverse effects; AGONIST THERAPY view to evaluate the effectiveness and dropouts; dropouts due to adverse ef- harms of pharmacologic treat- fects; treatment discontinuation be- Efficacy of dopamine agonists ments for patients with primary RLS. cause of adverse effects; specific ad- was evaluated in 18 randomized, This report is based on research con- verse effects; and augmentation. double-blind, placebo-controlled We used criteria developed by the studies10-27 and 2 comparative effec- ducted by the Minnesota Evidence- 7 based Practice Center under con- Cochrane Collaboration in rating in- tiveness studies.28,29 Two placebo- tract to the Agency for Healthcare dividual RCTs as good, fair, or poor controlled studies26,27 and 1 com- quality based on the adequacy of allo- Research and Quality (AHRQ) and parative effectiveness trial29 assessed 6 cation concealment, blinding, report- is available on the AHRQ web site. ing of reasons for attrition, and how cabergoline (an ergot-derived dopa- analyses accounted for incomplete mine agonist). Cabergoline is not METHODS data (eAppendices 2-4). Using meth- FDA approved for RLS treatment and ods developed by AHRQ and the Effec- is rarely used in the United States 8 STUDY SELECTION tive Health Care Program, we evalu- owing in part to FDA warnings about ated overall strength of evidence for cardiac valvular complications. For outcomes for each treatment compari- We included randomized controlled this reason, we did not include 2 cab- son based on the criteria of risk of bias, trials (RCTs) that enrolled individuals ergoline placebo–controlled stud- consistency, directness, and precision. with primary RLS as defined by the ies26,27 with the other dopaminergic We resolved discrepancies in quality and IRLS Study Group.1,3 Eligible trials strength of evidence ratings by discus- trials. We describe findings of the were published in English, evaluated sion and consensus. single comparative effectiveness trial pharmacologic interventions for RLS of cabergoline vs levodopa because vs placebo or active intervention, DATA SYNTHESIS it is one of two comparative effec- lasted at least 4 weeks, and reported tiveness studies identified29; the validated RLS symptom or QoL scale AND ANALYSIS scores, clinician and patient global other was a crossover trial compar- impact scale scores, or measures of For trials that included similar popula- ing pramipexole to dual-release le- 28 sleep quality. We limited interventions, interventions, and outcomes and vodopa-benserazide. Sixteen pla- tions to drugs approved for use for that presented sufficient data, we cal- cebo-controlled dopamine agonists any condition in the United States. culated pooled random-effects esti- (n=4861) were included, 5 evalu-

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671 Articles included for title/abstract review fect in the 4 fixed-dose studies of 283 RCTs 14,22-24 388 Observational studies rotigotine or pramipexole. Overall, evidence was high strength. 573 Articles excluded after review of title and abstract Visual inspection of funnel plots and Egger test did not demonstrate pub- 98 Articles included for full-text screening lication bias (Egger intercept 2-sided 69 Articles excluded P = .20) (eAppendix 6). 4 Duration 14 Not an intervention of interest Cabergoline improved IRLS 18 No outcome of interest scores more than levodopa in a single 7 Nonrandomized study design 1 No comparator comparative effectiveness trial last- 1 Not a primary study 24 Not pharmacologic interventions for primary RLS ing 30 weeks (n = 361) among adults with severe symptoms (mean IRLS 29 RCTs included in analysis score, 25.7) (WMD, Ϫ7.0 points [95% CI, Ϫ9.1 to Ϫ4.9]) (moderate- strength evidence).29 One small Figure 1. Study flow diagram. RCTs indicates randomized controlled trials; RLS, restless leg syndrome. crossover comparative effective- ated pramipexole10-14; 7, ropini- IRLS Responders ness trial (n = 39) compared prami- role15-21; and 4, rotigotine22-25 (Ն50% Score Reduction) pexole with dual-release levodopa- (Table 1 and eTable 1). Only 2 benserazide in newly diagnosed, trials lasted 24 weeks or more,22,24 The proportion of IRLS responders previously untreated patients over and none exceeded 28 weeks. The was significantly greater with dopa- two 4-week periods.28 Overall re- overall mean age of participants was mine agonist therapy compared with ductions of IRLS scores from base- 55 years, and 65% were women. placebo (61% vs 41%) (RR, 1.60 line trended toward significant im- Nearly all (96%) participants in the [95% CI, 1.38 to 1.86]; NNT, 4.9) provement with pramipexole 7 trials that reported race were ( Figure 2) (high-strength 10,12-14,17,22,24 12-14,22-25 treatment, with a mean reduction of white. evidence). There was no evi- 7.2 points compared with 4.0 points Most studies required at least dence of a difference in treatment ef- for levodopa-benserazide (P = .054). “high-moderate” to “severe” symp- ficacy between the pramipexole and The subset of patients with severe tom severity (most trials required an rotigotine (eTable 2). IRLS scale score of Ն15 [IRLS scale RLS (IRLS baseline score, 21-30) range, 0-40] at baseline and some re- Responders on CGI Scale and showed significant reductions in quired a score Ͼ20) with frequent Mean Change From Baseline IRLS scores with pramipexole vs le- symptom occurrence and duration in the IRLS Scale Score vodopa/benserazide (P = .047) (low- of at least 1 month. Mean symptom strength evidence). severity was “severe” at baseline, The proportion of responders (with with an overall mean IRLS scale a rating of “much improved” or “very QoL and Patient-Reported score of 25.1. Duration of RLS var- much improved”) in the CGI scale Sleep Outcomes ied with a mean of 17 years for ro- was greater for dopamine agonist pinirole to 2 years for rotigotine therapy (68%) than for placebo Overall high-strength evidence dem- trials. Trials enrolled patients who (46%) (RR, 1.45 [95% CI, 1.36 to onstrated that dopamine agonists were newly diagnosed as well as 1.55]; NNT, 4.4; 15 trials).10-14,16-25 improved QoL and self-reported those who had and had not re- Visual inspection of funnel plots and sleep measures compared with pla- ceived prior RLS treatments. Egger test did not demonstrate pub- cebo. Dopamine agonist improved More than half (60%) of pa- lication bias (Egger intercept 2-sided RLS specific QoL as measured by tients in rotigotine trials had re- P = .32) (eAppendix 5). SMDs in RLS QoL scale scores. The ceived previous RLS treatment, vs Treatment with dopamine ago- effect size was small to medium in 26% and 44% for pramipexole and nists resulted in a small reduction in magnitude (SMD, 0.37 [95% CI, ropinirole, respectively. Seven trials symptom severity based on mean 0.27 to 0.48]; 9 trials)10,12,14,17,21-25 excluded patients with augmenta- change from baseline between treat- (eFigure 2). Results were similar tion and/or end-of-dose rebound ment and placebo in IRLS scale during previous RLS treatment. scores. Mean change in the IRLS across types of dopamine agonist Study drugs were given orally on a score favored active treatment treatment. Dopamine agonists im- daily (rather than “as-needed”) ba- (WMD, Ϫ4.56 points [95% proved patient-reported sleep qual- sis, with the exception of rotigo- CI,Ϫ5.42 to Ϫ3.70]; 14 ity compared with placebo as mea- tine, which was delivered transder- trials)10-14,16-18,20-25 (eFigure 1). The sured by the Medical Outcomes mally each day. Most studies used magnitude of reduction in IRLS scale Study sleep problem index (MOS) flexible up-titration based on symp- scores was greater with rotigotine scale (SMD, 0.38 [95% CI, 0.29 to tom response and adverse effects. therapy22-25 than with pramipex- 0.46]; 8 trials)10,17,18,20-24 (eFigure 3). Four studies investigated multiple ole10-14 or ropinirole treatment16-18,20,21 The magnitude of effect was small fixed doses of the drug.14,22-24 (test for interaction, P = .02). We to moderate.

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Summary Statistics, Outcome, Source/Treatments Trials, No. Patients, No. RR, WMD, or SMD (95% CI) NNT or NNH IRLS responders (Ն50% score reduction)11-13,21-24 All trials vs placebo 7 2218 RR 1.60 (1.38 to 1.86) NNT 4.9 Pramipexole 3 1079 RR 1.46 (1.22 to 1.74) NNT 5.9 Rotigotine 4 1139 RR 1.76 (1.47 to 2.10) NNT 3.8 CGI scale responders: (much–very much improved)9-13,15-24 All trials vs placebo 15 4446 RR 1.45 (1.36 to 1.55) NNT 4.4 Pramipexole 5 1747 RR 1.61 (1.40 to 1.86) NNT 3.8 Ropinirole 6 1608 RR 1.37 (1.25 to 1.50) NNT 5.7 Rotigotine 4 1091 RR 1.37 (1.22 to 1.54) NNT 5.0 IRLS total score: mean change from baseline9-13,15-17,19-24 All trials vs placebo 14 3578 WMD Ϫ4.56 (Ϫ5.42 to Ϫ3.70) NNT NA Pramipexole 5 1578 WMD Ϫ4.76 (Ϫ6.24 to Ϫ3.28) NNT NA Ropinirole 5 1517 WMD Ϫ3.49 (Ϫ4.44 to Ϫ2.54) NNT NA Rotigotine 4 585 WMD Ϫ6.09 (Ϫ7.71 to Ϫ4.46) NNT NA RLS quality of life9,11,13,16,20-24 All trials vs placebo 9 2140 SMD 0.37 (0.27 to 0.48) NNT NA Pramipexole 3 912 SMD 0.43 (0.25 to 0.61) NNT NA Ropinirole 2 643 SMD 0.30 (0.14 to 0.45) NNT NA Rotigotine 4 585 SMD 0.37 (0.13 to 0.60) NNT NA Self-rated sleep MOS-SPI-II9,16,17,19-23 All trials vs placebo 8 2052 SMD 0.38 (0.29 to 0.46) NNT NA Pramipexole 1 356 SMD 0.36 (0.15 to 0.57) NNT NA Ropinirole 4 1237 SMD 0.37 (0.24 to 0.49) NNT NA Rotigotine 3 459 SMD 0.43 (0.24 to 0.61) NNT NA Study withdrawals due to an adverse event9-24 All trials vs placebo 16 4860 RR 1.37 (1.03 to 1.82) NNH 24.6 Pramipexole 5 1791 RR 0.97 (0.69 to 1.35) NNH Ϫ763.7 Ropinirole 7 1698 RR 1.48 (0.99 to 2.20) NNH 27.8 Rotigotine 4 1370 RR 2.50 (1.33 to 4.70) NNH 11.2 Patients with Ն1 adverse event9-24 All trials vs placebo 16 4854 RR 1.19 (1.12 to 1.28) NNH 7.6 Pramipexole 5 1790 RR 1.16 (1.04 to 1.29) NNH 8.0 Ropinirole 7 1695 RR 1.20 (1.10 to 1.32) NNH 8.7 Rotigotine 4 1369 RR 1.25 (1.00 to 1.59) NNH 7.1

Outcome, Source/Treatments Risk of Biasa Directnessa Precisiona Consistencya Evidence Ratingb IRLS responders (Ն50% score reduction)11-13,21-24 All trials vs placebo Low Direct Precise Consistent High Pramipexole Low Direct Precise Consistent High Rotigotine Low Direct Precise Consistent High CGI scale responders: (much–very much improved)9-13,15-24 All trials vs placebo Low Direct Precise Consistent High Pramipexole Low Direct Precise Consistent High Ropinirole Low Direct Precise Consistent High Rotigotine Low Direct Precise Consistent High IRLS total score: mean change from baseline9-13,15-17,19-24 All trials vs placebo Low Direct Precise Consistent High Pramipexole Low Direct Precise Consistent High Ropinirole Low Direct Precise Consistent High Rotigotine Low Direct Precise Consistent High RLS quality of life9,11,13,16,20-24 All trials vs placebo Low Direct Precise Consistent High Pramipexole Low Direct Precise Consistent High Ropinirole Low Direct Precise Consistent High Rotigotine Low Direct Precise Consistent High Self-rated sleep MOS-SPI-II9,16,17,19-23 All trials vs placebo Low Direct Precise Consistent High Pramipexole Low Direct Precise Unknown Moderate Ropinirole Low Direct Precise Consistent High Rotigotine Low Direct Precise Consistent High Study withdrawals due to an adverse event9-24 All trials vs placebo Low Direct Precise Consistent High

(continued)

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Outcome, Source/Treatments Risk of Biasa Directnessa Precisiona Consistencya Evidence Ratingb Pramipexole Low Direct Imprecise Consistent Moderate Ropinirole Low Direct Imprecise Consistent Moderate Rotigotine Low Direct Precise Consistent High Patients with Ն1 adverse event9-24 All trials vs placebo Low Direct Precise Consistent High Pramipexole Low Direct Precise Inconsistent Moderate Ropinirole Low Direct Precise Consistent High Rotigotine Low Direct Precise Consistent High

Abbreviations: CGI, clinician-assessed global impression; IRLS, International Restless Legs Syndrome; MD, mean difference; MOS-SPI-II, Medical Outcomes Scale–Sleep Problems Index II; NA, not applicable; NNH, number needed to harm; NNT, number needed to treat; RLS, restless leg syndrome; RR, relative risk; SMD, standardized mean difference; WMD, weighted mean difference (a negative SMD and WMD indicates that the active treatment is more effective than placebo). a The strength of the evidence was evaluated based on 4 required domains: (1) risk of bias, whether the studies for a given outcome or comparison have good internal validity, reflects the aggregate quality of the trials evaluated; (2) consistency is the degree of similarity in the effect sizes, ie, same direction of effect, of the included studies; (3) directness indicates a single, direct link between the intervention of interest and the outcome; and (4) precision is the degree of certainty surrounding an effect estimate of a given outcome. b Strength of evidence was rated using the following grades: (1) high confidence indicated that further research is very unlikely to change the confidence in the estimate of effect, meaning that the evidence reflects the true effect; (2) moderate confidence denoted that further research may change our confidence in the estimate of effect and may change the estimate; (3) low confidence indicated that further research is very likely to have an important impact on the confidence in the estimate of effect and is likely to change the estimate, meaning that there is low confidence that the evidence reflects the true effect; and (4) insufficient, indicating that the evidence was unavailable or did not permit a conclusion.

DAs Placebo RR (95% CI) RR (95% CI) Study or Subgroup Events, No. Total Events, No. Total Weight, % M-H, Random M-H, Random

1.1.1 Pramipexole studies Montagna et al,12 2011 154 203 114 199 24.8 1.32 (1.15-1.53) Oertel et al,13 2007 117 224 33 114 13.4 1.80 (1.32-2.47) Winkelman et al,14 2006 157 254 36 85 16.0 1.48 (1.12-1.90) Subtotal (95% CI) 681 398 54.3 1.46 (1.22-1.74) Total event, No. 428 183 τ2 χ2 2 Heterogeneity: = 0.01; 2 = 3.51 (P = .17); I = 43% Test for overall effect: Z = 4.19 (P <.001)

1.1.2 Rotigotine studies Hening et al,22 2010 (1-3 mg) 177 297 37 99 15.7 1.59 (1.22-2.09) Oertel et al,25 2008 (1-3 mg) 112 117 22 53 12.3 1.52 (1.09-2.14) Oertel et al,23 2010 35 46 7 20 5.0 2.17 (1.17-4.04) Trenkwalder et al,24 2008 183 333 29 114 12.7 2.16 (1.55-3.00) Subtotal (95% CI) 853 286 45.7 1.76 (1.47-2.10) Total events, No. 507 95 τ2 χ2 2 Heterogeneity: = 0.00; 3 = 3.19 (P = .36); I = 6% Test for overall effect: Z = 6.20 (P <.001)

Total (95% CI) 1534 684 100.0 1.60 (1.38-1.86) Total events, No. 935 278 τ2 χ2 2 Heterogeneity: = 0.02; 6 = 11.70 (P = .07); I = 49% Test for overall effect: Z = 6.10 (P <.001) 0.2 0.5 1.0 2.0 5.0 χ2 2 Test for subgroup differences: 1 = 2.13 (P = .14); I = 53.1% Favors Placebo Favors DA

Figure 2. Dopamine agonists (DAs) vs placebo. Proportion of participants reporting greater than 50% reduction in mean International Restless Legs Syndrome score from baseline. M-H indicates Mantel-Haenszel; RR, risk ratio.

CALCIUM CHANNEL was 51 years, and nearly all (94%) blind gabapentin enacarbil treat- ALPHA-2-DELTA LIGANDS were white. Women constituted 60% ment were then randomized to of participants. The overall mean continuing gabapentin enacarbil treat- Calcium channel alpha-2-delta li- baseline IRLS scale score was 24. The ment or placebo in a 12-week double- gands were evaluated in 7 random- mean RLS disease duration was 12 blind phase.31 ized, double-blind, placebo- years. One study was a maintenance controlled studies (N = 1096)30-36 trial in which responders (defined as IRLS Responders (Table 2 and eTable 3) including the having an IRLS score Ͻ15 that had (Ն50% Score Reduction) prodrug gabapentin enacarbil,30-33 decreased by Ն6 points compared pregabalin,34,35 or gabapentin.36 None with baseline and having been rated Calcium channel alpha-2-delta li- of the trials lasted longer than 12 “much improved” or “very much im- gand therapy was superior to pla- weeks. The mean age of participants proved” on the CGI scale) to single- cebo in increasing the proportion of

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Summary Statistics, Outcome, Source/Treatments No. of Trials Patients, No. RR, WMD, or SMD (95% CI) NNT or NNH IRLS responders (Ն50% score reduction)29,33,34 All trials vs placebo 3 503 RR 1.66 (1.33 to 2.09) NNT 4.1 Gabapentin enacarbil 1 321 RR 1.54 (1.18 to 2.01) NNT 4.7 Pregabalin 2 182 RR 2.03 (1.33 to 3.11) NNT 3.4 CGI scale responders: (much–very much improved)29,31,33 All trials vs placebo 3 662 RR 1.60 (1.21 to 2.10) NNT 3.2 Gabapentin enacarbil 2b 538 RR 1.80 (1.51 to 2.14) NNT 3.0 Pregabalin 1 124 RR 1.14 (0.80 to 1.64) NNT 11.1 IRLS total score: mean change from baseline29,31,33 All trials vs placebo 3 475 WMD Ϫ4.26 (Ϫ5.75 to Ϫ2.77) NNT NA Gabapentin enacarbil 2a 431 WMD Ϫ4.18 (Ϫ5.76 to Ϫ2.60) NNT NA Pregabalin 1 44 WMD Ϫ4.90 (Ϫ9.41 to Ϫ0.39) NNT NA Self-rated sleep MOS-SPI-II29,31 Gabapentin enacarbil 2 431 SMD 0.53 (0.33 to 0.72) NNT NA Patients with Ն1 adverse event29-31,33,34 All trials vs placebo 5 933 RR 1.17 (0.1.00 to 1.36) NNH 8.6 Gabapentin enacarbil 3 738 RR 1.09 (0.1.00 to 1.19) NNH 9.5 Pregabalin 2 195 RR 1.67 (0.74 to 3.80) NNH 4.0

Outcome, Source/Treatments Risk of Biasa Directnessa Precisiona Consistencya Evidence Ratingb IRLS responders (Ն50% score reduction)29,33,34 All trials vs placebo Low Direct Precise Consistent High Gabapentin enacarbil Low Direct Precise Unknown Moderate Pregabalin Low Direct Precise Consistent High CGI scale responders: (much–very much improved)29,31,33 All trials vs placebo Low Direct Precise Consistent High Gabapentin enacarbil Low Direct Precise Consistent High Pregabalin Low Direct Imprecise Unknown Low IRLS total score: mean change from baseline29,31,33 All trials vs placebo Low Direct Precise Consistent High Gabapentin enacarbil Low Direct Precise Consistent High Pregabalin Low Direct Precise Unknown Moderate Self-rated sleep MOS-SPI-II29,31 Gabapentin enacarbil Low Direct Precise Consistent High Patients with Ն1 adverse event29-31,33,34 All trials vs placebo Low Direct Imprecise Consistent Moderate Gabapentin enacarbil Low Direct Precise Consistent High Pregabalin Low Direct Imprecise Consistent Moderate

Abbreviations: CGI, clinician-assessed global impression; IRLS, International Restless Legs Syndrome; MD, mean difference; MOS-SPI-II, Medical Outcomes Scale–Sleep Problems Index II; NA, not applicable; NNH, number needed to harm; NNT, number needed to treat; RR, relative risk; SMD, standardized mean difference; WMD, weighted mean difference (a negative SMD and WMD indicates that the active treatment is more effective than placebo). a The strength of the evidence was evaluated based on 4 required domains: (1) risk of bias, whether the studies for a given outcome or comparison have good internal validity, reflects the aggregate quality of the trials evaluated; (2) consistency is the degree of similarity in the effect sizes, ie, same direction of effect, of the included studies; (3) directness indicates a single, direct link between the intervention of interest and the outcome; and (4) precision is the degree of certainty surrounding an effect estimate of a given outcome. b Strength of evidence was rated using the following grades: (1) high confidence indicated that further research is very unlikely to change the confidence in the estimate of effect, meaning that the evidence reflects the true effect; (2) moderate confidence denoted that further research may change our confidence in the estimate of effect and may change the estimate; (3) low confidence indicated that further research is very likely to have an important impact on the confidence in the estimate of effect and is likely to change the estimate, meaning that there is low confidence that the evidence reflects the true effect; and (4) insufficient, indicating that the evidence was unavailable or did not permit a conclusion.

IRLS responders (61% vs 37%; RR, rated improved or very much im- Mean change in IRLS score from base- 1.66 [95% CI, 1.33 to 2.09]; NNT, proved on the CGI scale (74% vs 44%; line in the crossover trial by Winkel- 4.1) (Figure 3). The evidence was RR, 1.60 [95% CI, 1.21 to 2.10]; NNT, man et al33 significantly favored gab- high strength (eTable 2). 3.2; 3 trials).30,32,34 Improvement was apentin enacarbil (WMD, Ϫ6.6 points significant for gabapentin enacarbil [95% CI,Ϫ8.6 to Ϫ4.6]). In the main- Responders on the CGI Scale and therapy30,32 but not for pregabalin tenance trial, patients continuing gab- Mean Change From Baseline treatment34 (test for interaction, apentin enacarbil therapy were sig- in The IRLS Scale Score P = .03) (high-strength evidence). nificantly less likely to experience Pooled weighted mean change in IRLS relapse (defined as an increase by Ն6 A significantly greater proportion of score from baseline vs placebo was points from randomization to a IRLS patients allocated to calcium chan- Ϫ4.26 points (95% CI, Ϫ5.75 to score Ն15 points and a rating of nel alpha-2-delta ligand therapy were Ϫ2.77; 3 trials)30,32,34 (eFigure 4). “much worse” or “very much worse”

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 A-2-DLs Placebo RR (95% CI) RR (95% CI) Study or Subgroup Events, No. Total Events, No. Total Weight, % M-H, Random M-H, Random

2.1.1 Gabapentin enacarbil Lee et al,30 2011 137 225 38 96 71.6 1.54 (1.18-2.01) Subtotal (95% CI) 225 96 71.6 1.54 (1.18-2.01) Total events, No. 137 38 Heterogeneity: Not applicable Test for overall effect: Z = 3.14 (P = .002)

2.1.2 Pregabalin Allen et al,34 2010 61 103 5 21 8.4 2.49 (1.14-5.44) Garcia-Borreguera et al,35 2010 22 30 11 28 19.9 1.87 (1.12-3.10) Subtotal (95% CI) 133 49 28.4 2.03 (1.33-3.11) Total events, No. 83 16 Heterogeneity: τ2 = 0.00; χ2 = 0.41 (P = .52); I 2 = 0% 1 Test for overall effect: Z = 3.26 (P =.001)

Total (95% CI) Total events, No. τ2 χ2 2 358 145 100.0 1.66 (1.33-2.09) Heterogeneity: = 0.00; 2 = 1.57 (P = .46); I = 0% Test for overall effect: Z = 4.40 (P <.001) 220 54 χ2 = 2 Test for subgroup differences: 1 = 1.18 (P .28); I = 15.1% 0.1 0.2 0.5 1.0 2.0 5.0 10.0 Favors Placebo Favors A-2-DL

Figure 3. Calcium channel alpha-2-delta ligands (A-2-DLs) vs placebo. Proportion of participants reporting a greater than 50% reduction in mean International Restless Legs Syndrome score from baseline. M-H indicates Mantel-Haenszel; RR, risk ratio.

on the CGI scale) than patients allo- lower with placebo—not a statisti- 4.48 [95% CI, 2.68 to 7.48]; NNH, cated to placebo, 9% and 23%, re- cally significant difference (P = .11). 19.7; 8 trials),15,16,20-22,25 and somno- spectively (RR, 0.41 [95% CI, 0.20 to Evidence was low strength. lence (12% vs 6%; RR, 2.04 [95% CI, 0.85]; NNT, Ϫ7.5).31 Two gabapen- 1.50 to 2.76]; NNH, 16.6; 8 tin enacarbil trials reported signifi- SHORT-TERM HARMS trials)11,14,15,17,18,20,22,23 (overall high- cantly improved sleep adequacy based strength evidence for these out- on the MOS sleep adequacy domain Forest plots for study withdrawals comes). Application site reactions (SMD, 0.53 [95% CI, 0.33 to and adverse events are shown in eFig- were much more common with 0.72]).30,32 The magnitude of effect ures 5-17. Patients were less likely to transdermal rotigotine than with pla- was considered moderate and withdraw from dopamine agonists cebo, 29% vs 3%, respectively (RR, strength of evidence high. than from placebo (20% vs 24%; RR, 8.32 [95% CI, 3.45 to 20.05]; NNH, 0.79 [95% CI, 0.66 to 0.94]; NNH, 3.9; 4 trials) (high-strength MISCELLANEOUS Ϫ29.9; 16 trials) (moderate- evidence).22-25 PHARMACOLOGIC STUDIES strength evidence).10-25 There was a Patients allocated to calcium chan- significant increase in study with- nel alpha-2-delta ligands were less Two miscellaneous pharmacologic drawals due to adverse effects asso- likely to withdraw from treatment ow- studies assessed adults with moder- ciated with dopamine agonist treat- ing to any reason compared with pa- ate to severe RLS.37,38 One small ment (10% vs 6%; RR, 1.37 [95% tients allocated to placebo (12% vs short-term RCT (n = 46) found that CI,1.03 to 1.82]; NNH = 24.6; 16 17%; RR, 0.71 [95% CI, 0.52 to 0.99]; intravenous iron (ferric carboxy- trials) (high-strength evidence).10-25 NNH, Ϫ20.6; 5 trials)30-32,34,35 (high- maltose) significantly improved IRLS Risk of withdrawal due to adverse strength evidence). Compared with symptom scale scores compared events differed between dopamine placebo, alpha-2-delta ligands were with placebo over 28 days of agonists (test for interaction, P = .02) associated with an overall nonsignifi- therapy37 in adults without iron de- with the highest increase associated cant increase in study withdrawals ficiency. Mean improvements for with rotigotine (RR, 2.50 [95% CI, due to adverse effects (8% vs 4%; RR, iron and placebo were reductions of 1.33 to 4.70]; NNH, 11.2), primar- 1.86 [95% CI, 0.95 to 3.63]; NNH, 8.9 and 4.0 points, respectively, with ily due to application site reactions. 22.1; 4 trials)30,32,34,35 (moderate- a mean difference of Ϫ4.90 (95% More patients reported at least 1 ad- strength evidence). CI,Ϫ9.27 to Ϫ0.53). The evidence verse effect with dopamine agonist Short-term effects that were sig- strength was moderate. Ferric compared with placebo (74% vs 61%; nificantly greater with calcium chan- carboxymaltose also significantly RR, 1.19 [95% CI, 1.12 to 1.28]; nel alpha-2-delta ligands compared improved CGI, RLS QoL, and sleep NNH, 7.6; 16 trials) (high-strength with placebo were somnolence (19% measures (MOS total score) vs evidence).10-25 vs 3%; RR, 5.37 [95% CI, 2.38 to placebo. Short-term adverse effects from 12.12]; NNH, 6.0; 5 trials),30,32,34-36 One small RCT evaluated the an- treatment with dopamine agonists unsteadiness or dizziness (17% vs tidepressant bupropion.38 The IRLS compared with placebo were nau- 4%; RR, 4.11 [95% CI, 2.19 to 7.71]; symptom scores after 6 weeks com- sea (23% vs 7%; RR, 3.31 [95% CI, NNH, 7.8; 4 trials),30,32,34,35 and dry pared with baseline were 10.4 points 2.53 to 4.33]; NNH, 6.7; 15 mouth (6% vs 1%; RR, 3.31 [95% CI, lower with bupropion and 7.6 points trials),11-25 vomiting (7% vs 2%; RR, 1.09 to 10.05]; NNH, 20.3; 4

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 trials).30,34-36 Evidence for these out- nists and alpha-2-delta ligands. sign, and method used to ascertain comes was high strength. Preliminary results from a 12-week augmentation. Little data exist on Three subjects each reported di- placebo-controlled, 52-week ac- long-term adherence and adverse ef- arrhea (12.5%) and blood phospho- tive-comparator trial (n = 719) in- fects for alpha-2-delta ligands. rus decrease (12.5%) with intrave- dicated that pregabalin was more For individuals unable to initi- nous iron therapy.37 No subjects in effective than pramipexole in im- ate or tolerate dopamine agonist or the placebo arm reported these proving RLS symptoms.42 alpha-2-delta ligands, or for whom events. Two patients allocated to bu- Trial results may lack broad these drugs have failed, recom- propion and 1 to placebo discontin- generalizability. Exclusion criteria mended pharmacologic treatments ued treatment owing to nausea.38 No were many. Subjects were typically include off-label opioids (mor- other adverse events were reported. recruited from RLS clinics rather phine, oxycodone, and metha- than primary care or mental health done), sedative hypnotics, and tra- COMMENT settings; frequent sites for detec- madol. We found no eligible studies tion and management of individu- evaluating these agents, and none are als with suspected RLS. Enrollees FDA approved for RLS treatment. All Results from small, placebo- had greater disease severity, fre- have the potential for long-term controlled randomized trials of gen- quency, and duration than re- abuse, especially given the subjec- erally short duration in selected pa- ported by the estimated 1.5% of tive nature of RLS symptoms and tients with “high-moderate” to individuals described as “RLS suf- the large placebo response seen in “severe” RLS symptoms of long du- ferers” based on a telephone survey other pharmacologic studies. Evi- ration demonstrated that dopa- of adults who agreed to be inter- dence on additional options is lim- mine agonists and alpha-2-delta li- viewed about RLS. No RCTs as- ited to 4 lower-quality trials. These gands were effective. They increased sessed patients with mild or mod- trials provide low-strength evi- the percentage of individuals with erate disease, and few lasted longer dence for a benefit with compres- primary RLS responding to treat- than 6 months. None enrolled in- sion stockings,43 near-infrared ment, reduced RLS symptoms, and dividuals younger than 18 years, light,44 and strength training and improved disease-specific QoL and and nearly all enrollees were white. treadmill walking,45 but not for the patient-reported sleep outcomes. Ad- Studies rarely provided details to botanical extract valerian.46 verse effects and long-term treat- assess if secondary causes were ad- We urge caution in applying our ment withdrawals due to adverse ef- equately excluded such as iron de- findings to the more heteroge- fects or lack of efficacy were ficiency or renal insufficiency. neous population of patients with common. Our findings provide in- Treatment withdrawal for any rea- RLS in primary care settings. The dependent evidence that adds to pre- son was greater in patients as- populations enrolled in these trials vious work evaluating RLS treat- signed to placebo compared with had RLS of high-moderate to se- ments.39,40 Our report includes active intervention, suggesting that vere intensity for many years; many evidence published through June short-term treatment benefits ex- participants had received previous 2012, focuses on pharmacologic ceeded harms among enrollees. unsuccessful drug treatment for RLS. therapies for patients with primary However, patient acceptability re- In contrast, individuals presenting RLS, and emphasizes clinically rel- garding the tradeoff of benefits to to primary care with new RLS-like evant outcomes. Our findings pro- harms may differ in patients not symptoms may have milder symp- vide information about the clinical enrolled in trials, individuals with toms or other conditions for which benefits and harms of pharmaco- less severe RLS, or those treated for symptoms mimic RLS (eg, periodic logic therapies especially relevant to a long duration. leg movement disorders, nocturnal primary care providers needing man- Clinicians and patients should be leg cramps, vascular or neurogenic agement guidance for patients they aware of the large placebo re- claudication). They may also be diagnose with RLS. sponse. Long-term observational younger or older or have more co- All studies administered thera- studies reporting withdrawals due to morbidities than subjects included pies daily rather than “as needed.” loss of efficacy or adverse effects also in available RCTs. Applicability con- Although the effectiveness, harms, suggest that pharmacologic treat- cerns are more salient in light of di- and adherence to as-needed therapy ment benefits are not sustained over rect-to-consumer marketing that has are unknown, current recommen- time for many patients with RLS and raised awareness of potential RLS dations note this as an option.41 that these treatments result in ad- symptoms.47 Evidence is lacking about the long- verse effects leading to discontinu- In conclusion, among individu- term effectiveness in, and applica- ation.7 Withdrawal from mostly als with primary RLS and high- bility to, adults with less-severe dopamine agonist and levodopa moderate to very severe RLS symp- or less-frequent RLS symptoms, treatment was common, occurring toms of long duration, dopamine nonwhite and older adults, those in 13% to 57% of subjects owing to agonists and alpha-2-delta ligands with multiple comorbidities, and either lack of efficacy or adverse ef- increased the percentage of those children. fects. Long-term augmentation “responding to treatment,” re- We found no peer-reviewed ranged from 2.5% to 60% and var- duced RLS symptom scores, and im- RCT data on the comparative ben- ied markedly by type of dopamine proved patient-reported sleep out- efits or harms of dopamine ago- agonist, follow-up time, study de- comes, disease-specific QoL, and

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 overall RLS impact compared with Administrative, technical, and mate- 12. Montagna P, Hornyak M, Ulfberg J, et al. Ran- placebo. Adverse effects and treat- rial support: Wilt, MacDonald, and domized trial of pramipexole for patients with restless legs syndrome (RLS) and RLS-related ment withdrawals due to adverse ef- Rutks. Study supervision: Wilt, Kha- impairment of mood. Sleep Med. 2011;12(1): fects for dopamine agonists and al- waja, and Butler. 34-40. pha-2-delta ligands were common. Conflict of Interest Disclosures: 13. Oertel WH, Stiasny-Kolster K, Bergtholdt B, et al; We found no high-quality data on None reported. Pramipexole RLS Study Group. Efficacy of prami- comparative effectiveness and harms Funding/Support: This study re- pexole in restless legs syndrome: a six-week, mul- ticenter, randomized, double-blind study (effect- of commonly used treatments nor ef- ceived funding from the Agency for RLS study). Mov Disord. 2007;22(2):213-219. fectiveness data on other interven- Healthcare Research and Quality 14. Winkelman JW, Sethi KD, Kushida CA, et al. tions often used but lacking FDA ap- (contract No. 290-2007-10064-I). Efficacy and safety of pramipexole in restless legs proval for RLS treatment. In addition, Online-Only Material: The eAppen- syndrome. Neurology. 2006;67(6):1034-1039. 15. Adler CH, Hauser RA, Sethi K, et al. Ropinirole for long-term efficacy and adherence as dices, eTables, and eFigures are avail- restless legs syndrome: a placebo-controlled well as applicability to adults with able at http://www.jamainternalmed crossover trial. Neurology. 2004;62(8):1405- less-frequent or less-severe RLS .com. 1407. symptoms, adult with more recent 16. Benes H, Mattern W, Peglau I, et al. 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