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Guideline Update
August 2012 An important update in the recommendation about the use of rotigotine for the treatment of signs and symptoms associated with moderate-to-severe primary restless legs syndrome (RLS) is included in a letter to the editor that was published after the American Academy of Sleep Medicine (AASM) Board of Directors approved the practice parameters. This letter to the editor is an essential supplement to the practice parameters document: Aurora RN; Kristo DA; Bista SR; Rowley JA; Zak RS; Casey KR; Lamm CI; Tracy SL; Rosenberg RS.LEEP 2012;35(8):1037. TREATMENT OF RLS AND PLMS DISORDER IN ADULTS: PRACTICE PARAMETERS
The Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder in Adults—An Update for 2012: Practice Parameters with an Evidence- Based Systematic Review and Meta-AnalysesAn American Academy of Sleep Medicine Clinical Practice GuidelineR. Nisha Aurora, MD1; David A. Kristo, MD2; Sabin R. Bista, MD3; James A. Rowley, MD4; Rochelle S. Zak, MD5; Kenneth R. Casey, MD, MPH6; Carin I. Lamm, MD7; Sharon L. Tracy, PhD8; Richard S. Rosenberg, PhD81Johns Hopkins University, School of Medicine, Baltimore, MD; 2University of Pittsburgh, Pittsburgh, PA; 3University of Nebraska Medical Center, Omaha, NE; 4Division of Pulmonary, Critical Care, and Sleep Medicine, Wayne State University School of Medicine, Detroit, MI; 5Sleep Disorders Center, University of California, San Francisco, San Francisco CA; 6Cincinnati Veterans Affairs Medical Center, Cincinnati, OH; 7Children's Hospital of NY–Presbyterian, Columbia University Medical Center, New York, NY; 8American Academy of Sleep Medicine, Darien, IL A systematic literature review and meta-analyses (where appropriate) were performed to update the previous AASM practice parameters on the treatments, both dopaminergic and other, of RLS and PLMD. A considerable amount of literature has been published since these previous re- views were performed, necessitating an update of the corresponding practice parameters. Therapies with a STANDARD level of recommendation include pramipexole and ropinirole. Therapies with a GUIDELINE level of recommendation include levodopa with dopa decarboxylase inhibitor, opioids, gabapentin enacarbil, and cabergoline (which has additional caveats for use). Therapies with an OPTION level of recommendation include carbamazepine, gabapentin, pregabalin, clonidine, and for patients with low ferritin levels, iron supplementation. The committee recommends a STANDARD AGAINST the use of pergolide because of the risks of heart valve damage. Therapies for RLS secondary to ESRD, neuropathy, and superficial venous insufficiency are discussed. Lastly, therapies for PLMD are reviewed. However, it should be mentioned that because PLMD therapy typically mimics RLS therapy, the primary focus of this review is therapy for idiopathic RLS.
Keywords: Restless legs syndrome, RLS, periodic limb movement disorder, PLMD, sleep-related movement disorders
Citation: Aurora RN; Kristo DA; Bista SR; Rowley JA: Zak RS; Casey KR; Lamm CI; Tracy SL; Rosenberg RS. The treatment of restless legs
syndrome and periodic limb movement disorder in adults—an update for 2012: practice parameters with an evidence-based systematic review and nostic criteria. The four cardinal diagnostic features of RLS The purpose of this review is to survey and provide an evidence- include (1) an urge to move the limbs that is usually asso- based update of the literature and corresponding practice parame- ciated with paresthesias or dysesthesias, (2) symptoms that ters in the area of the treatment of restless legs syndrome (RLS) and start or become worse with rest, (3) at least partial relief of periodic limb movement disorder (PLMD). Two previous reviews symptoms with physical activity, and (4) worsening of symp- have been published by the American Academy of Sleep Medicine toms in the evening or at night. RLS frequently also has a (AASM): the first was in 1999 and cal ed "The Treatment of Rest- primary motor symptom that is characterized by the occur- less Legs Syndrome and Periodic Limb Movement Disorder,"2 and rence of periodic leg movements in sleep (PLMS). PLMS oc- the most recent was published in 2004 cal ed "An Update on the cur in approximately 80% to 90% of patients who have RLS Dopaminergic Treatment of Restless Legs Syndrome and Periodic and support the diagnosis of RLS. These criteria are based on Limb Movement Disorder."3 Two practice parameters have also the published report by Allen et al.7 (IRLS) from a workshop been published: "Practice Parameters for the Dopaminergic Treat- held at the National Institutes of Health and are endorsed ment of Restless Legs Syndrome and Periodic Limb Movement by the ICSD-2.
Disorder"4 and "Practice Parameters for the Treatment of Restless PLMD is characterized by periodic episodes of repetitive Legs Syndrome and Periodic Limb Movement Disorder."5 limb movements during sleep, which most often occur in the lower extremities, including the toes, ankles, knees, and hips, and occasionally in the upper extremities. These movements may be associated with an arousal, and if so, sleep disrup- tion can cause excessive daytime sleepiness. PLMD is thought Most studies published after 2003 reference either the to be rare as PLMS are typically associated with RLS, REM ICSD-26 or the International RLS Study Group (IRLS)7 diag- sleep behavior disorder (RBD), or narcolepsy and represent a distinct diagnosis from PLMD.6 It should be noted that while an extensive amount of literature on the treatment of RLS has Submitted for publication February, 2012
emerged since the prior practice parameter update, the data on Submitted in final revised form February, 2012
therapy for PLMD has essentially remained unchanged. Due Accepted for publication February, 2012
to the scarcity of PLMD therapy data and the fact that the Address correspondence to: Department of Science and Research, Amer- occurrence of only PLMD is uncommon, the current practice ican Academy of Sleep Medicine, 2510 North Frontage Road, Darien, parameter primarily focuses on the therapies for RLS, while IL 60561; Tel: (630) 737-9700 ext.9332; Fax: (630) 737-9790; E-mail: recommendation levels are not given for pharmacological therapies for PLMD.
SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al 2.2 Treatment Efficacy Measures
for RLS with fewer than 10 subjects completing the study and Due to the multifaceted nature of RLS, many different treat- for treatments of PLMD with fewer than 5 subjects completing ment efficacy measures have been used to assess RLS severity, the study were rejected. Also, studies with less than 1 week of sleep quality, and quality of life, both subjectively and objec- treatment time were rejected. A total of 378 hits were obtained tively. There is some consensus in recent studies to focus on the and supplemented by pearling. The final number of articles in- IRLS rating scale8 (IRLS) and the Clinical Global Impression cluded for all treatments with either benefit/efficacy or harm (CGI) scale.9 Both of these are subjective rating scales. The data is 126.
IRLS was validated in 2003.8 It consists of a 10-question assess- ment of RLS in a format of 0 to 4, 0 being "never" or "none," 3.2 PICO Questions
and 4 being "very severe" or "very often." The severity of RLS PICO (Population, Intervention, Comparison, Outcome)
is rated as: 1-10 mild; 11-20 moderate; 21-30 severe; and 31- questions were developed for the review, and are summarized 40 very severe. The CGI has 3 sections: (1) Severity of illness; (2) Global improvement (CGII) or change (CGIC), and (3) Ef- ficacy index. Most, if not all, studies document the proportion of patients with an investigator-rated score of "much improved" To compare the range of treatment options available for RLS (2) or "very much improved" (1) on the CGI-I (or –C) scale and PLMD, one outcome measure was chosen for which the (defined as a "response" on this 7-point overall global improve- majority of studies presented data: the International Restless ment scale, a non-disease specific outcome measure in which 1 Legs Syndrome Rating Scale (IRLS). Data on other outcomes = very much improved and 7 = very much worse).
measures besides IRLS are summarized and presented in a de- Other subjective measures include the RLS-6, which was scriptive manner for further information for the reader. Thus used typically prior to 2003, the Patient Global Impression for medications that were studied prior to the development of (PGI), the Sleep Questionnaire Form A, Quality of Life (QoL) the IRLS, meta-analysis was not performed. All meta-analyses for RLS, the Augmentation Severity Rating Scale (ASRS), Vi- were performed using MIX software.11,12 All analyses are pre- sual Analog Scales (VAS), and the Medical Outcomes Study sented using the random effects model.
sleep scale (MOS). A variety of other scales have been used The result of each meta-analysis is shown in a figure with occasionally such as the Self-Rating Zung Depression Scale several components. Each study of the meta-analysis is identi- (SDS) and Anxiety Scale (SAS), the SF-36 (MOS short form fied along the left-hand column (study ID), and adjacent to it is health survey), the work productivity and activity impairment the year of the study, treatment (exposed, "e") results, and con- (WPAI) survey, the Pittsburgh Sleep Quality Index (PSQI), trol ("c") results. The results are expressed as "n/M/SD" cor- the Hospital Anxiety and Depression Scale (HADS), subjec- responding to "number/mean/standard deviation." A graphical tive sleep and awakening quality scale (SSA), and the Epworth representation of the data is shown in the center of the figure. Sleepiness Scale (ESS).
The vertical red line indicates the average response of all stud- The only objective measurements included are sleep-re- ies. The zero line represents no effect. The width of the red lated parameters by polysomnography (PSG) or actigraphy. diamond at the bottom of the plot represents the standard devia- The most salient include Periodic Limb Movements in Sleep tion of the meta-analysis. If the red diamond does not touch the (PLMS), PLM index (PLMI), PLMs arousal index (PLMS-AI), zero line, the meta-analysis results indicate that the treatment is and sleep efficiency.
different from zero (i.e., it has an effect). The magnitude of the effect across all studies is given by the value of the association 3.0 METHODS
measure along with the 95% confidence intervals.
Tables of the data used in the meta-analyses are presented at 3.1 Literature Search
the end of the manuscript in the Appendix.
The literature search was performed using a combination of MeSH terms and keywords. The MeSH terms were Rest- 3.4 Quality of Evidence
less Legs Syndrome and Nocturnal Myoclonus Syndrome. The The assessment of evidence quality was performed accord- keywords were: restless legs syndrome, periodic limb move- ing to the Grading of Recommendations Assessment, Develop- ment disorder, PLMD, sleep-related movement disorder(s), leg ment and Evaluation (GRADE) process. The GRADE system motor activity, myoclonic hyperkinesias, nocturnal myoclo- differs from other grading systems as each study is not only nus syndrome, RLS, periodic leg movement(s), periodic limb evaluated for study design and risk of bias, but, additionally, an movement(s), sleep leg movement(s), and PLM. All therapies estimate of effect (see footnote following article) is generated were searched with a start date of 11-1-1997 (6 months prior to for each outcome. Multiple aspects of quality are assessed in- previous search). Results on dopaminergic treatments between cluding study limitations, imprecision, inconsistency of results, 11-1-97 to 11-1-2001 already covered in the 2004 update were indirectness of evidence, and likeliness of publication bias. The excluded. The Cochrane Highly Sensitive Search Strategy10 for quality of evidence from observational studies can be adjust- identifying randomized trials in MEDLINE was applied to the ed by the presence of large magnitudes of effect, evidence of search. The search was performed first on August 12, 2010, and dose-response associations, and all plausible confounders that updated again on June 29, 2011, to capture the latest literature. increase the confidence in the estimated effects.13 Quality refers The limits of the search were: humans, English, all adults (no to the confidence that the estimates of the effects are correct, pediatrics), randomized controlled trials (RCTs), and no edito- and the quality rating is applied to a body of evidence and not rials, letters, comments, or case reports. Studies on treatments to individual studies.1 SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al Table 1—PICO question parameters
Comparison
Adults diagnosed with Control group, those Subjective measures: RLS using the ICSD-2 with untreated RLS, or 1. IRLS rating scale or the International RLS those with RLS using an 2. Clinical Global Impression (CGI) Scale Study Group (IRLS) alternate treatment diagnostic criteria 4. Patient Global Impression (PGI) 5. Sleep Questionnaire Form A Gabapentin Enacarbil 6. Quality of Life (QoL) for RLS 7. Augmentation Severity Rating Scale (ASRS) 8. Visual Analog Scales (VAS) 9. Medical Outcomes Study Sleep Scale (MOS) 10. Self-Rating Zung Depression Scale (SDS) Iron supplementation 11. Anxiety Scale (SAS) 13. Work productivity and activity impairment (WPAI) 14. Pittsburgh Sleep Quality Index (PSQI) 15. Hospital Anxiety and Depression Scale (HADS) 16. Subjective sleep and awakening quality scale (SSA) 17. Epworth Sleepiness Scale (ESS) Objective measures: 1. Sleep-related parameters by polysomnography d. Sleep efficiency f. % TIB without leg movements 2. Sleep-related parameters by actigraphy b. Sleep efficiency Briefly, risk of bias includes aspects of study design (ran- consistency, indirectness, imprecision, and other considerations domized control trials [RCTs] versus non-randomized con- that went into the quality of evidence for each outcome of inter- trolled trials or before-after trials)14 and conduct such as est. Also reported are the number of patients that were studied, blinding, allocation concealment, large loss to follow-up, or the overall effect that was calculated in the meta-analysis (re- selective outcome reporting.15 Imprecision refers to wide con- ported as the mean difference [MD]), and a qualitative assess- fidence intervals around the estimate of effect when there are ment of the relative importance of the outcome.
relatively few patients and few events. Indirectness occurs One reviewer extracted the data and graded the studies and when the question being addressed is different than the avail- another verified this compiled information. The systematic re- able evidence regarding population, intervention, comparator, view of the evidence was additionally reviewed by an outside or outcome. There is inconsistency when there is unexplained expert who was an author on both previous review papers (2004 heterogeneity of the results. Reporting bias can occur if there and 1999). The AASM Standards of Practice Committee (SPC) is selective reporting of studies or outcomes, which may occur then reviewed the assessments of bodies of evidence as well.
if the published evidence is limited to a small number of trials funded by a for-profit organization.15 3.5 Strength of Recommendations
As a first step, all individual studies were assessed by 2 The SPC devel oped these practice parameters based on task force members for study design, and limitations to valid- the strength of evidence for efficacy of each therapy coun- ity (bias) for each outcome of interest.16,17 Randomized control terbalanced by an assessment of the relative benefits of each trials (RCTs) were considered a higher level of evidence than treatment versus the potential risks as delineated in Table 3. observational, nonrandomized, or before-after interventional The Board of Directors of the AASM subsequently approved studies (Table 2). Subsequently, the body of evidence for each these practice parameters. All members of the AASM SPC outcome was assessed and graded, taking into account the re- and Board of Direc tors completed detailed conflict-of-inter- sults of the meta-analysis (if applicable) and other factors as est statements and were found to have no conflicts of interest described above. The final assessment, as defined in Box 1, was with regard to this subject. The recommendations were also determined for each treatment and outcome measure.
critically reviewed by an outside expert, and the concerns that The results are reported as evidence profiles in each section were raised were addressed by the SPC prior to approval by that include the number of studies, study design, limitations, in- SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al Table 2—A summary of GRADE's approach to rating quality of evidence1
Initial quality of a
Quality of a body
Study design
body of evidence
Higher if
of evidence
−2 Very serious Moderate (three plus: +1 Evidence of a gradient −2 Very serious All plausible residual confounding Observational studies +1 Would reduce a demonstrated effect +1 Would suggest a spurious effect if no −2 Very serious effect was observed Very Low (one plus: −1 Serious−2 Very serious −1 Likely−2 Very likely Table 3—AASM levels of recommendations
Overall quality of evidence
Benefits clearly outweigh harm/burden
Benefits closely balanced with harm/burden
uncertainty in the estimates of benefit/harm/burden
Harm/burden clearly outweighs benefits
Assessment of benefit/harm/
The AASM expects these guidelines to have an impact on Box 1—Final assessments of level of bodies of evidence1
pro fessional behavior, patient outcomes, and, possibly, health High: We are very confident that the true effect lies close to that of
care costs. These practice parameters reflect the state of knowl- the estimate of the effect.
edge at the time of publication and will be reviewed, updated, and revised as new information becomes available. Defini- Moderate: We are moderately confident in the effect estimate: The
true effect is likely to be close to the estimate of the effect, but there is tions of levels of recommendations used by the AASM appear a possibility that it is substantially different.
in Table 3. Particularly noteworthy on this table is that when harm/burden clearly outweighs benefit, a STANDARD level of Low: Our confidence in the effect estimate is limited: The true effect
recommendation against the proposed therapy is given regard-
may be substantially different from the estimate of the effect.
less of the overall quality of evidence. Sections titled "Values
Very low: We have very lit le confidence in the ef ect estimate: The true
and Trade-offs" ap pear under each individual practice pa-
ef ect is likely to be substantial y dif erent from the estimate of ef ect.
rameter. The Values and Trade-offs discussion elucidates the
rationale leading to each recommendation. These sections are
an integral part of the GRADE system and offer transparency
These practice parameters define principles of practice that to the process.18
should meet the needs of most patients in most situations. These guidelines should not, however, be considered inclusive of all 4.0 RECOMMENDATIONS FOR THERAPIES FOR RLS
proper methods of care or exclusive of other methods of care The salient detailed data from the studies was extracted and reasonably directed to obtaining the same results. The ultimate can be found in evidence tables, available at http://www.aasmnet.
judgment regarding propriety of any specific care must be org/practiceguidelines.aspx. Table 4 shows a summary of the rec- made by the physician, in light of the individual circumstances ommendation statements organized by strength of recommenda- presented by the patient, available diagnostic tools, accessible tion, including the body of evidence level, the assessment of the treatment options, and resources.
harm/benefit balance and the FDA status of the intervention.
SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al Table 4—Summary of recommendation statements
Strength of
Evidence
FDA status
Standards for use in RLS
Clinicians should treat patients with RLS with Benefits clearly outweigh harms Clinicians should treat patients with RLS with ropinirole.
Benefits clearly outweigh harms Standards against use in RLS
Clinicians should not treat RLS patients with pergolide Harms clearly outweigh benefits because of the risks of heart valve damage.
Guidelines for use in RLS
Clinicians can treat RLS patients with levodopa with Benefits closely balanced with dopa decarboxylase inhibitor.
harms. This is particularly true for but off-label those with intermittent RLS who use this medication sporadically.
Clinicians can treat RLS patients with opioids.
Benefits clearly outweigh harms Clinicians can treat patients with RLS with gabapentin Uncertainty in balance between Approved for benefits and harms Given the potential of side effects, including heart Benefits closely balanced with valve damage, clinicians can treat RLS patients with cabergoline only if other recommended agents have been tried first and failed, and close clinical follow-up is Options for use in RLS
Clinicians may treat RLS patients with gabapentin.
Unclear benefit/harm balance Clinicians may treat patients with RLS with pregabalin.
Benefits closely balanced with Clinicians may treat RLS patients with carbamazepine.
Benefits closely balanced with Clinicians may treat RLS patients with clonidine.
Unclear benefit/harm balance Clinicians may use supplemental iron to treat RLS Unclear benefit/harm balance patients with low ferritin levels.
There is insufficient evidence at present to evaluate the use of pharmacological therapy in patients diagnosed with PLMD alone.
4.1 Introduction to Therapies for RLS
nitude of this effect at 40%. This reinforces the need for placebo- There are 2 types of therapies for RLS: pharmacotherapy and controlled studies to determine the true effect of any treatment.
non-pharmacotherapy. The use of pharmacotherapy has been more widespread. Newer non-pharmacotherapies, such as cognitive be- havioral therapy or exercise therapy, are stil being investigated.
One interesting recent study has highlighted the importance of 4.2.1 Dopaminergic medications
the placebo effect in RLS studies. Fulda and Wetter19 performed Overall, dopaminergic agents are the most extensively inves- a meta-analysis on the treatment of RLS and estimated the mag- tigated and used therapies for the treatment of RLS. Since the SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al Weight (%)
with 95% CI
-6.1 (-7.6382 to -4.5618) -9.7 (-14.1384 to -5.2616) -11 (-16.3815 to -5.6185) -3.8 (-5.7398 to -1.8602) -6.6 (-8.7122 to -4.4878) -10.9 (-15.0367 to -6.7633) -4.5 (-7.2689 to -1.7311) 100.00% -6.7262 (-8.4937 to -4.9586) Figure 1—Meta-analysis of pramipexole IRLS data, improvement over placebo.
Summary of findings
No of patients
studies Design Limitations
IRLS Rating Scale (follow-up 3 to 12 weeks; range of scores: 0-40; Better indicated by lower values)
possible reporting (4.9 to 8.5 lower) Figure 2—Evidence profile for pramipexole.
prior practice parameter update, the literature has advanced con- VAS.31 In patients with RLS-related mood disturbance, Mon- siderably with regards to both the number and quality of studies tagna et al.36 also reported an improvement in mood impairment for dopaminergic treatment of RLS. While these agents confer (Beck Depression Inventory II). In patients with RLS and mood many benefits, there are some adverse effects that should be impairment, Hornyak et al.40 reported a statistically significant recognized. Similar to patients with Parkinson's disease, RLS decrease in RLS-related limb pain as assessed by VAS. Lastly, patients treated with dopamine agonists may develop dopamine Inoue et al.37 reported that older age and mild RLS severity were dysregulation syndrome.20-25 These patients may exhibit an ad- significantly associated with early response to low-dose prami- dictive pattern of dopamine replacement therapy use and/or pexole therapy in their study of Japanese patients.
behavioral disturbances including punding and impulse control A meta-analysis was performed on all RCT studies with pla- disorders such as pathologic gambling, compulsive shopping, cebo control, and the results are shown in Figure 1. The results compulsive eating, and hypersexuality. One report20 indicated a show an average improvement of 6.7 points (95% CI 4.9 to 8.5) prevalence of 7% for pathologic gambling and 23% for compul- in the IRLS scale with pramipexole use over placebo. The trials sive eating in RLS subjects treated with a dopaminergic medica- with larger patient populations trend toward an approximate im- tion. Case reports indicate that discontinuation of the dopamine provement of 5 points. Figure 2 summarizes the evidence profile.
agonist results in resolution or improvement of the impulse The long-term studies (open label, 26 to 52 weeks in length) control disorder,26-28 although these patients may be particularly report a 17-point improvement in IRLS scores over baseline susceptible to dopamine agonist withdrawal syndrome.29 The le- with pramipexole use. See the online supplement at http://www.
vodopa review encompassed an aggregate of medications with aasmnet.org/practiceguidelines.aspx for the detailed data.
varying dopa decarboxylase inhibitor types (DDCI).
Some other studies have been published that were low level evidence (Saletu et al.,41 Stiasny-Kolster and Oertel,42 Silber et 4.2.1.1 Non-ergot derived dopamine agonist: pramipexole
al.43), and all reported improvements in RLS symptoms with The dopamine agonist pramipexole is effective in the treat- pramipexole use. The study by Trenkwalder et al.44 on the ef- ment of moderate-to severe RLS. (Level of evidence: High) This fects of pramipexole withdrawal after 6 months of use showed recommendation was a guideline in the previous practice pa- that patients switched to placebo experienced worsening symp- rameter. An additional 8 short-term studies30-37 (3 to 12 weeks) toms over those who continued to receive pramipexole.
of treatment of patients with moderate-to-severe idiopathic RLS Pramipexole is well tolerated.30-34,36,45 Inoue et al.,38 Mon- and 2 studies38,39 on long-term efficacy up to 1 year have been tagna et al.,36 and Partinen et al.39 also reported that adverse published. All studies showed improved RLS symptom severity events (AEs) were mild to moderate in intensity and typical for according to IRLS30-37 as well as other measures of RLS includ- non-ergot dopamine agonists. These included nausea and som- ing: MOS sleep disturbance and sleep adequacy30; CGI-I30-32,34,37; nolence, which typically decreased in frequency over time, and PGI-I30,33,34,37; RLS QoL30,31,33; PLM index33-35; PSQI37; and nasopharyngitis. Winkelman and Johnston46 and Silber et al.43 SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al Weight (%)
with 95% CI
-11.7 (-16.6402 to -6.7598) -2 (-7.1813 to 3.1813) -3.9 (-5.2659 to -2.5341) -3 (-5.0245 to -0.9755) -2.5 (-4.6017 to -0.3983) 100.00% -3.9876 (-5.9688 to -2.0063) Figure 3—Meta-analysis of ropinirole IRLS data, improvement over placebo.
Summary of findings
No of patients
IRLS Rating Scale (follow-up 2-12 weeks; measured with: Points; range of scores: 0-40; Better indicated by lower values)
Possible reporting MD 4.0 lower (2.0 Figure 4—Evidence profile for ropinirole.
reported that augmentation occurred in one-third of the patients stead of baseline; and Garcia-Borreguero et al.56 reported a on extended pramipexole use, but was manageable by earlier non-randomized treatment trial without placebo control. All dosing in the day, small dose increases,46 or increased doses data can be found in the online supplement at http://www.
earlier in the day.43 Silver et al.47 reported that (1) over 10 years the average annual rate of augmentation leading to discontinua- The data from the RCT studies were combined into a meta- tion of pramipexole was 7% in the 164 patients studied; (2) the analysis. The average improvement in IRLS score over placebo percentage continuing medication over 5 years was 58%; and was 4 points (95% CI: 2 to 6) as shown in Figure 3. The body (3) the daily dose of pramipexole at the time of discontinuation of evidence level is judged to be high. The evidence profile is for augmentation, as opposed to all other reasons, was 1.28 ± summarized in Figure 4.
1.0 vs. 0.66 ± 0.5 mg. Trenkwalder et al.44 reported no augmen- The patients had moderate-to-severe idiopathic RLS. Eight tation after 9 months of use in 150 patients, and Inoue et al.38 studies showed significant improvement with ropinirole versus reported no augmentation in 140 patients after 1 year of use.
placebo on IRLS48-52,54-56 and other measures (RLS symptom diary,48 PLMS,52,53 PLM with arousal,53 PLM while awake,53 4.2.1.1a: Clinicians should treat patients with RLS with
ability to initiate sleep,53 sleep adequacy [MOS],49,50,53,56 PLMI [actigraphy],49 CGII responders,49,50,54,56 PGI,54 MOS sleep Values and Trade-Offs: Pramipexole is upgraded to stan-
disturbance,50,55,56 MOS somnolence,50,55,56 MOS sleep quan- dard from the previous practice parameter based on multiple tity,50,55,56 RLS QoL,50,55,56 anxiety [HADS],49 WPAI,56 SF-36,56 studies showing efficacy in RLS. Pramipexole is typically well and patient relapse55).
tolerated and side effects are self-limited with cessation of Ropinirole is also effective in the treatment of severe-to-very severe RLS. This conclusion is based on an analysis of pooled data57 from four 12-week clinical trials49-51,53 of 223 patients 4.2.1.2 Non-ergot derived dopamine agonist: ropinirole
with IRLS scores ≥ 24 compared to those receiving placebo (n The dopamine agonist ropinirole is effective in the treat- = 240). The mean treatment difference was > 3 points in these ment of moderate-to-very severe RLS (Level of evidence: patients. An increasing treatment effect with ropinirole and not High). This recommendation was an option in the previous placebo was reported with increasing RLS severity. Additional practice parameter. Since then an additional 5 RCTs 48-52 have improvements in global symptoms, sleep, and quality of life been published. The studies were well conducted and reported were also reported.
consistent results, with just one48 outlier as shown in Figure Two studies did not show greater efficacy than placebo. 3. This study included only 22 patients. Four other studies re- Although IRLS was significantly better than baseline in the 4 ported results that could not be used in the meta-analysis: Al- weeks of open testing by Bliwise et al.,52 no difference compared len et al.53 gave only the adjusted treatment difference without to placebo was noted after an additional 2 weeks of randomized any standard deviations or details; Kushida et al.54 provided testing. Allen also reported a nonsignificant effect of ropinirole imprecise data with very large standard deviations; Montplai- on IRLS after 12 weeks.53 Unfortunately, the data were not re- sir et al.55 reported results compared to 24 weeks treated in- ported in a format that allowed inclusion in the meta-analysis.
SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al Ropinirole was found to be effective48-51,53,55,56 and generally entacapone 150/37.5/200 mg reduced PLMs during the second well tolerated.48-51,55,56 The most common side effects were nau- half (P = 0.06 and P < 0.001, respectively) or the last 3 h of the sea,48,50,52-54,56 headache,50,52-54,56 dizziness,48,53 somnolence,52,54 night (P < 0.05 and P < 0.01, respectively). Single doses of LCE and vomiting.54 Adverse events led to discontinuation in 8.7% with up to 150 mg L-dopa were effective and also well tolerated of patients in one study.56 The incidence of augmentation was without typical side effects such as nausea. Of note, Stalevo is reported to be between 0%50,51 and 2.3%.56 The mean daily dose on an FDA watch list with concerns about possible increased ranged from 1.551 to 4.648 mg/d taken 1-3 hours before bed- risk of both prostate cancer and cardiovascular disease.
time50,51,53 or in divided doses.54 A significant placebo effect was Hogl et al.61 reported during a 6-month multi-center, open-la- reported in one study.54 bel trial with flexible dosing of levodopa that augmentation with L-dopa occurred in 60% of the patients and caused 12% to dis- 4.2.1.2a: Clinicians should treat patients with RLS with
continue treatment by 6 months. The median time to occurrence of augmentation was 71 days. Compared to those without aug- Values and Trade-Offs: This recommendation is upgraded
mentation, patients with augmentation were significantly more to standard from the previous practice parameter based on mul- likely to be on higher doses of levodopa (≥ 300 mg, 83 vs. 54%, tiple studies with RCT data showing efficacy in RLS therapy. P = 0.03) and to show less improvement of symptom severity.
Ropinirole is typically well tolerated and side effects are self limited with cessation of ropinirole therapy.
4.2.1.3a: Clinicians can treat RLS patients with levodopa with
dopa decarboxylase inhibitor. (GUIDELINE)
Values and Trade-Offs: This recommendation is changed
Levodopa is effective in the treatment of RLS, but carries from the previous practice parameter, where it was given a the risk of augmentation (Level of evidence: High). This con- STANDARD level of recommendation for use. Levodopa has clusion and evidence level is based primarily on the data from longstanding clinical use in RLS with concomitant concerns for the previous review paper.3 Since the last review in 2004, new daytime RLS augmentation and early morning rebound of RLS formulations of levodopa have been studied (combinations of symptoms. The use of levodopa may be most advantageous sustained and regular release L-dopa58,59 or Stalevo,60 which for those patients with intermittent RLS symptoms that do not contains L-dopa, carbidopa, and entacapone [LCE]) and there require daily therapy. For those that require daily therapy for has been progress in understanding augmentation.61 The newer RLS, the newer dopaminergic agents may be a better choice. studies were limited by short duration RCT but followed by an Therapy should be tailored to the individual patient's specific open clinical trial (Saletu et al.58), outcome measures other than circumstances and needs. Vigilance for secondary impulsive IRLS reported (Polo et al.60), nonrandomized and open label behavior as an adverse reaction is needed.
(Hogl et al.61 and Trenkwalder et al.59).
Both Trenkwalder et al.59 and Saletu et al.58 found impro- 4.2.1.4 Ergot-derived dopamine agonists: pergolide and
vements in RLS symptoms with the combination of sustained release (sr) and regular release (rr) L-dopa, although Trenkwal- The dopamine agonist pergolide is effective in the treatment der et al. found that roughly 66% of the subjects terminated of RLS but has been withdrawn in the U.S. because of the risk therapy before the end of a year due to probable augmentation. of cardiac valvulopathy. (Level of evidence: High) Although The dose at 1-year in the Trenkwalder study (mean rr-L-dopa determined as effective based on the previous review,3 per- 203 ± 101 mg with 185 ± 93 mg sr-L-dopa) was higher than the golide has been voluntarily withdrawn by the manufacturer in 4-week dose in the Saletu study (mean rr-L-dopa 100 ± 38.5 the United States because of risk of heart valve damage. Only 1 mg with 112 ± 33.2 mg sr-L-dopa). Trenkwalder reported im- study by Trenkwalder et al.62 has been published since the last proved quality of sleep, reduced sleep latency, increased total review was written. Pergolide was found to significantly reduce sleep time, reduced severity of RLS at time of falling asleep and PLMS-AI, PLMI, RLS severity (IRLS), CGI response, and during the night, but increased severity of RLS during the day. PGI response versus placebo; however, sleep efficiency did not Global improvement was found in 56% of patients, 30% were improve. The mean dose for the double-blinded patients was unchanged, and 9% were slightly worse. Saletu reported a sig- 0.52 ± 0.22 mg/d and for the open-label patients was 0.72 ± nificant reduction of PLM/h TST from 20.0 ± 14.7 to 4.5 ± 4.9 0.42 mg/d at 12 months. With regard to side effects; nausea and (P < 0.01), as well as reduction of all other objective RLS/PLM headache were more frequent with pergolide than with placebo. variables. However, treatment did not improve sleep efficiency The authors conclude that low-dose pergolide was well toler- or subjective sleep quality with respect to placebo. Other scales ated and maintained its efficacy in the long term.
(IRLS, PSQI, SSA, VAS) also improved significantly. Trenk- The dopamine agonist cabergoline is effective in the treat- walder et al.59 recommended that other treatments be sought if ment of moderate-to-severe RLS. (Level of evidence: High) more than 400 mg L-dopa is required to treat RLS patients.
The dopamine agonist cabergoline is more effective in the In a randomized controlled crossover trial of 2 days for each treatment of RLS than levodopa, but is not as well tolerated. treatment, Polo et al.60 studied Stalevo, a new formulation of L- (Level of evidence: Moderate) The recommendation was an dopa that potentially provides longer symptom control through- option in favor of cabergoline use in the previous practice out the night by incorporating entacapone. The mean PLMI parameter because of 1 low-level study. A significant amount and TIB were significantly reduced compared with placebo. of evidence63-66 has been published since the previous review. Compared with levodopa/carbidopa 100/25 mg, levodopa/car- These studies investigated the effects of cabergoline in patients bidopa/entacapone 100/25/200 mg and levodopa/carbidopa/ with moderate-to-severe idiopathic RLS and one in severe-to- SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al Weight (%)
with 95% CI
-23.7 (-28.7281 to -18.6719) -15.7 (-20.8022 to -10.5978) -17.1 (-18.4394 to -15.7606) -13.3 (-18.9268 to -7.6732) 100.00% -17.4916 (-20.9021 to -14.081) Figure 5—Meta-analysis of cabergoline IRLS data, before-after treatment.
Weight (%)
with 95% CI
-15.8 (-22.68 to -8.92) -12.4 (-18.3918 to -6.4082) 100.00% -13.8665 (-18.385 to -9.348) Figure 6—Meta-analysis of cabergoline IRLS data, improvement over placebo.
Summary of findings
No of patients
Limitations Inconsistency Indirectness Imprecision considerations
IRLS Rating Scale for RCTs (follow-up mean 5 weeks; measured with: points; range of scores: 0-40; Better indicated by lower values)
IRLS Rating Scale for Before-After data for all trials (follow-up 2 to 12 months; range of scores: 0-40; Better indicated by lower values)
2 RCT and very serious Figure 7—Evidence profile for cabergoline. 1Patients served as their own controls for before-after treatment effect.
very severe RLS patients.66 The average effective dose was ap- L-dopa was found to be better tolerated: 95% of patients on proximately 2 mg, at least 3 h before bedtime.64 All studies L-dopa vs. 85% on cabergoline were determined to have no or reported significant improvement in IRLS.63-66 The meta-analy- mild side effects.
sis of the before-after treatment data show an average decrease Cabergoline is primarily indicated in treatment of prolactino- in IRLS of 17.5 points (95% CI: 14 to 21 point improvement; ma with associated risk of visual field loss. Cabergoline carries see Figure 5), and the 2 RCTs show a decrease in IRLS of 1663 a comparatively much stronger risk-to-benefit ratio in prolacti- and 1264 with an average decrease of 14 (95% CI: 9 to 18 point noma therapy than that seen in RLS therapy. Cabergoline risks improvement] over the control group (Figure 6). Other sec- include valvular heart disease.68 The data seem to agree that ondary measures including PLMS-AI, PLM-I, PLMS-I, sleep there is valve risk, but the defined risk in each study varies by efficiency, sleep time, sleep quality,63,62 QoL, RLS-6 (day and incidence and degree of valve injury.68-75 Other side effects were night),63,64,66 CGI severity,63,62 sleep diaries,64 and nocturnal ac- mostly mild and transient and included nausea, dizziness, and tivity (actigraphy) also improved.62,65 Figure 7 summarizes the headache.66 If unacceptable gastrointestinal side effects were evidence profile.
experienced, domperidone could be prescribed.63 Some pos- An additional RCT67 compared the effect of cabergoline sible or probable mild augmentation was reported.64,66 versus levodopa. Direct comparison67 showed cabergoline to be superior to L-dopa with respect to efficacy (by IRLS, 4.2.1.4a: Clinicians should not treat RLS patients with pergolide
time to discontinuation of therapy or augmentation, RLS-6, because of the risks of heart valve damage. (STANDARD)
QoL, SF-A, CGI, and ASRS). In terms of IRLS, cabergoline Values and Trade-Offs: Pergolide risks include heart valve
showed an improvement over L-dopa of 6.6 (95% CI 8.6 to damage and retroperitoneal fibrosis making any future use of 4.7) points, and, versus baseline, of 15.6 ± 10.8. However, pergolide in RLS strongly contraindicated.
SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al Weight (%)
with 95% CI
-3.2 (-5.47 to -0.93) -7.2 (-10.97 to -3.43) -4.4 (-6.92 to -1.88) 100.00% -4.5 (-6.5 to -2.5) Figure 8—Meta-analysis of gabapentin enacarbil IRLS data, improvement over placebo.
Summary of findings
No of patients
IRLS Rating Scale (follow-up up to 12 weeks; measured with: Points; range of scores: 0-40; Better indicated by lower values)
Possible reporting controlled trials (2.5 to 6.5 lower) Figure 9—Evidence profile for gabapentin enacarbil.
4.2.1.4b: Given the potential of side effects, including heart
12 months, all of whom reported at least a 75% reduction in valve damage, clinicians can treat RLS patients with cabergoline
symptoms and no augmentation. Silver et al.47 reported no aug- only if other recommended agents have been tried first and
mentation leading to the end of treatment with methadone in a failed, and close clinical follow-up is provided. (GUIDELINE)
10-year retrospective review of 76 patients on methadone. The Values and Trade-Offs: The risks of cabergoline are suf-
median daily dose after 8-10 years on methadone treatment was ficient to recommend cabergoline not be used in routine clinical no more than 10 mg greater than at 6 months, indicating mini- practice for RLS particularly since there are multiple alternative mal change in narcotic requirement over time.
RLS dopaminergic therapies with a better side effect profile. Because the risk is unclear, it is prudent to remain cautious with 4.2.2a: Clinicians can treat RLS patients with opioids. (GUIDELINE)
respect to recommending cabergoline.
Values and Trade-Offs: Opioid data shows clinical effec-
tiveness in treating RLS with a low level of evidence. As men- 4.2.2 Opioid medications
tioned above, side effects can include an undefined potential for Opioids are effective in the treatment of RLS, especially for abuse in predisposed patients and a possible risk for the devel- patients with RLS that is not relieved by other treatments. (Lev- opment or worsening of sleep apnea. Therefore, patients should el of evidence: Low) In addition to 2 small RCTs that studied be clinically monitored for the development of symptoms. In oxycodone and propoxyphene discussed in the 1999 review,76,77 general, however, this medication is very well tolerated and has 3 new studies (1 open-label and 2 retrospective reviews) were a lower risk of augmentation than is seen in the dopaminergic found on the effects of opioids on RLS.78-80 Lauerma and Mark- kula78 reported that 10 of 12 patients found tramadol to be more effective than drugs they had tried in the past, 1 experienced 4.2.3 Anticonvulsant medications
some relief, and 1 had no relief. Some patients alternated tra- madol with levodopa or clonazepam while other patients took 4.2.3.1 Gabapentin enacarbil
"drug holidays" or used it intermittently to minimize concerns Gabapentin enacarbil is effective in the treatment of mod- of abuse. There is one report of augmentation with long-term erate-to-severe RLS. (Level of evidence: High) Four studies tramadol treatment.81 In a retrospective review of 113 patients provided data on the change in IRLS score with gabapentin on long-term (up to 5 years) opioid therapy (most commonly ti- enacarbil treatment over placebo.82-85 All were well-conducted lidine, dihydrocodeine, codeine, propoxyphene, or methadone), studies with no limitations. Three studies82,84,85 provided data Walters et al.79 reported that opioids seem to have long-term comparing the change in IRLS vs. baseline of 1200 mg/d of effectiveness in the treatment of RLS and PLMS, but patients gabapentin enacarbil vs. the same change with placebo. A meta- on long-term opioid therapy should be clinically or polysom- analysis was performed on these data. Two studies83,85 were 12 nographically monitored periodically for the development of weeks in duration, and 184 was only 2 weeks long. The meta- sleep apnea, as 3 of 7 subjects developed worsening sleep ap- analysis (Figure 8) showed an improvement in IRLS of −4.5 nea. Lastly, Ondo80 reported on the effect of methadone (5-40 over placebo (95% CI −6.5, −2.5). Other doses have also been mg/day) in 29 patients who had failed dopaminergics. Sixty- studied (60084,85and 180086 mg/d). All data are presented in the three percent of the patients remained on methadone for 23 ± Appendix. The evidence profile is shown in Figure 9.
SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al Summary of findings
No of patients
IRLS Rating Scale (follow-up 4-6 weeks; measured with: Points; range of scores: 0-40; Better indicated by lower values)
(7.4 to 12 lower) Figure 10—Evidence profile for gabapentin.
The studies also reported improvements in other out- indicated improvement in RLS symptoms. Although the pa- comes, including CGI-I,82,84,85 sleep architecture, mood,84 tient description was not explicitly defined, from the data it and sleep disturbance (MOS, PSQ, or WASO).82,84,85 A recent is judged that the patients in both studies were primarily in multicenter, randomized, double-blind, placebo-controlled, the mild-to-moderate category. In a randomized open clini- 2-period cross-over study87 reported the effect of 1200 mg/d cal trial, Happe et al.90 compared gabapentin to ropinirole gabapentin enacarbil on polysomnographically measured and found gabapentin to be as effective as ropinirole (IRLS, wake time during sleep and periodic limb movements with PLMS, and PLMS index significantly improved in both arousal per hour of sleep on 136 subjects after 4 and 10 weeks groups; ESS, QoL, and SAS were not significantly changed of treatment. There was a statistically significant decrease in in both groups; PLMS-AI, PSQI, and SDS were significantly both outcomes (adjusted mean treatment difference of −26 better in the gabapentin but not ropinirole groups). In a 12- minutes for wake time during sleep and −3.1 periodic limb week randomized cross-over trial (6 weeks for each treat- movements with arousal/h).
ment), Garcia-Borreguero et al.91 reported an improvement The short-term studies83,84 reported an increase in adverse in IRLS for gabapentin to 9.5 ± 6.1 versus placebo to 17.9 events over placebo of approximately 40%, whereas the ± 1.3 from a baseline of 20 for both groups. The evidence longer-term study82 reported an increase of only 8%. The profile is shown in Figure 10. Sleep studies showed a sig- most common adverse events were somnolence and dizzi- nificantly reduced PLMS index (11.3 ± 15.5 vs. 20.8 ± 15.5; ness, which were mild-to-moderate in intensity, and gener- P = 0.05) and improved sleep architecture. Patients whose ally remitted. A 52-week open label trial88 reported AEs in symptoms included pain benefited most from gabapentin. It 80.1% of subjects, 10.3% of which led to withdrawal from should be noted that gabapentin has the following potential the study. Most (67.7%) were mild-to-moderate in intensity, side effects: sedation, dizziness, vision changes, and suicidal while 3.5% were serious. An additional double-blind, place- behavior and ideation.
bo-controlled, 9-month study89 reported RLS relapse compar- ing maintenance on gabapentin enacarbil to withdrawal and 4.2.3.2a: Clinicians may treat RLS patients with gabapentin. (OPTION)
introduction of placebo in gabapentin enacarbil responders. Values and Trade-Offs: Low level evidence supports use of
Patients on gabapentin enacarbil had fewer relapses and lon- gabapentin for RLS therapy. Pain relief with gabapentin sup- ger time to relapse.
ports consideration of gabapentin in patients with both RLS and An additional consideration discussed by Ellenbogan et al.88 pain. There are some concerning potential side effects which is the following: although their study was not prospectively de- makes the balance of benefits versus harms uncertain.
signed to assess augmentation, there were no reported or sus- pected cases of augmentation based on a retrospective analysis of AEs. Also, there was no evidence of reemergence/rebound Pregabalin is effective in the treatment of moderate-to-se- of symptoms and no reports of compulsive behavior or impulse vere RLS. (Level of evidence: Low) Two studies have recently control disorder.
been published on the use of pregabalin to treat moderate- to-severe RLS. Allen et al.92 reported the results of a dose- 4.2.3.1a: Clinicians can treat patients with RLS with gabapentin
finding investigation of 50-450 mg/day over 6 weeks. There were 22-24 patients in each of 6 arms of the study. Calcula- Values and Trade-Offs: This is a new recommendation
tions indicated that 123.9 mg/day would provide 90% efficacy from the prior practice parameter. Sufficient evidence has in symptom reduction. Garcia-Borreguero et al.93 reported the emerged since the last practice parameter to support gabapen- results of a 12-week RCT of 30 patients randomized to prega- tin enacarbil as a guideline level for treatment in RLS therapy. balin and 28 to placebo. Twenty-four pregabalin and 19 pla- Gabapentin enacarbil therapy is generally well tolerated with cebo patients completed the trial. The baseline adjusted mean self-limited side effects. High level evidence is encouraging. difference in IRLS was 4.9 (95% CI 0.7 to 9.1) with a mean However, this medication is relatively new, thereby warranting dose of 337 mg/d. CGI-I showed significant improvements, a conservative recommendation level of guideline at this time.
as did measures of sleep quality and architecture including PLMS and PLMS-AI. Eighty-three percent of patients on pregabalin experienced AEs compared with 32% on placebo. Gabapentin is effective in the treatment of mild-to-mod- The most common AEs were unsteadiness (39% higher with erate RLS. (Level of evidence: Low) Two small studies pregabalin over placebo) and daytime sleepiness (29% higher (1690 and 2491 patients) were identified on gabapentin that with pregabalin over placebo). More information is needed SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al Summary of findings
No of patients
IRLS Rating Scale (follow-up up to 12 weeks; measured with: Points; range of scores: 0-40; Better indicated by lower values)
controlled trials (0.7 to 9.1 lower) Figure 11—Evidence profile for pregabalin.
regarding long-term use, including augmentation occurrence. ing et al.,2 are that "clonidine resulted in significant improvement Also, the effect of pregabalin on the working population is compared to baseline in subjective measures and sleep latency, needed.93 The optimal dose has not yet been identified.92,93 though PLMI was not significantly decreased. There was no cor- Figure 11 shows the evidence profile.
relation between plasma clonidine concentration and control of symptoms. Side effects were frequent (8 of 10 patients); however, 4.2.3.3a: Clinicians may treat patients with RLS with pregabalin
no patients left the study due to them." Side effects were generally considered mild, and included dry mouth, decreased cognition, Values and Trade-Offs: Preliminary data shows therapeu-
lightheadedness, sleepiness post dose, constipation, decreased li- tic efficacy in pregabalin therapy for RLS. However, long-term bido, and headache. Ausserwinkler and Schmidt98 reported that follow up and published experience in pregabalin therapy for "clonidine significantly improved RLS symptoms, with 8/10 pa- RLS is lacking. Thus, other better-studied RLS therapies should tients having complete relief of symptoms." be considered before prescribing pregabalin.
4.2.4a: Clinicians may treat patients with RLS with clonidine
Carbamazepine is effective in the treatment of RLS (Level of Values and Trade-Offs: Clonidine has minimal supporting
evidence: Low). This assessment is based on the data presented data in treating RLS and carries a considerable risk for side ef- in 1999, which are considered low according to the methods fects. Clonidine might be considered in treating hypertension of this update. Of the 3 studies, there was one large (n = 181 and RLS concomitantly. The risk of side effects (such as hypo- patients) but short-term (5 weeks) double-blind RCT94 with tension in normotensive patients) associated with clonidine in placebo control that showed carbamazepine to be significantly the treatment of RLS makes the benefit-to-harm ratio unclear.
more effective than placebo using a visual analogue scale. One study95 did not meet current inclusion criteria because the num- 4.2.5 Iron supplementation
ber of patients was too small (n = 6), and the other study was Iron supplementation has not been shown to be effective in a clinical series.96 No new evidence was found on the use of the treatment of RLS, except perhaps in patients with iron defi- carbamazepine since the last review (1999).
ciency or refractory RLS. (Level of evidence: Very low) There were 6 studies in total on 3 forms of iron treatment: 4.2.3.4a: Clinicians may treat RLS patients with carbamazepine.
oral iron sulfate, IV iron sucrose, and IV iron dextran. Over- all, the data are conflicting, but show some improvement in Values and Trade-offs: This has been downgraded from
select cases, typically those with low serum ferritin levels. GUIDELINE in the prior practice parameter to OPTION in this Davis et al.99 and Wang et al.100 studied oral iron sulfate. Da- practice parameter. Although carbamazepine efficacy in RLS vis et al. reported no significant effect on quality after 12 was shown in prior studies, these data are dated with no new weeks. Wang et al. also examined the use of oral iron sulfate. additional supportive work. There are other RLS therapies with In an RCT with 18 patients with low serum ferritin levels, the comparatively more supportive evidence, risk-to-benefit ratios, investigators showed a statistically significant improvement and clinical experience than carbamazepine. The benefits of car- in IRLS with 2 doses of 325 mg/d. Earley et al.101 and Grote et bamazepine therapy are closely balanced with potential adverse al.102 assessed 1000 mg iron sucrose administered in 2 doses side effects which include sedation, liver abnormalities and, of 500 mg or 5 doses of 200 mg. Earley et al. stopped the rarely, the potential suicidal ideation and behavior, and Stevens- trial early (after 2 weeks) because of no effect demonstrated Johnson syndrome.
on the global rating scale and PLMS. Grote et al. reported on patients with variable degrees of iron deficiency at sev- 4.2.4 Medications acting on the adrenergic systems
eral lengths of follow up including 2 months and 12 months. Clonidine is ef ective in the treatment of RLS (Level of evidence: There was no statistically different change in IRLS observed Low). No new evidence was found on the use of clonidine since at either endpoint. The dropouts for lack of treatment effect the last complete review2 where there were 2 small studies of 1197 were higher in the placebo group (61% vs. 17%). The use of and 2098 patients. The studies were also short-term (3 days98 to 2-3 IV iron dextran for treatment of RLS has also been examined. weeks97). Both were double-blind and placebo controlled, but ran- Earley et al.103 and Ondo104 investigated IV iron dextran. The domization was unclear in one.98 Because of these limitations and study by Earley et al. consisted of 11 patients and was open- other considerations, the data using the current methodology is label. Results were mixed. Ondo reported on 25 subjects in considered low. The results of Wagner et al.,97 as reported by Hen- a retrospective review of severe refractory RLS. It was dem- SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al Weight (%)
with 95% CI
-5.3 (-7.6656 to -2.9344) -6.6 (-11.7037 to -1.4963) -8 (-10.9407 to -5.0593) -8.2 (-10.6902 to -5.7098) -7.7 (-13.3902 to -2.0098) 100.00% -7.0222 (-8.4025 to -5.6419) Figure 12—Meta-Analysis of rotigotine IRLS data, improvement over placebo.
Summary of findings
No of patients
IRLS Rating Scale (follow-up 1 week to 6 months; measured with: Points; range of scores: 0-40; Better indicated by lower values)
(5.6 to 8.4 lower) Figure 13—Evidence profile for rotigotine.
onstrated that iron dextran can dramatically improve refrac- 4.3.1 Non-ergot-derived dopamine agonists: rotigotine
tory RLS, but results were inconsistent and not predicted by Rotigotine as a transdermal patch is effective in the treat- patient demographics. Anaphylactic symptoms are a risk. ment of moderate-to-severe RLS, but was withdrawn from the In 2009, the FDA issued a warning that analphylactic-type U.S. in 2008 (Level of evidence: High). This is a new treatment reactions, including fatalities, have followed the parenteral since the last review, and the evidence base is 5 studies107-111 for administration of iron dextran injection. The boxed warning the meta-analysis. No limitations were noted with the studies, recommends administering a test dose prior to the first thera- and the results were consistent. All data are presented in the on- peutic dose and observing reactions. However, it should be line supplement at http://www.aasmnet.org/practiceguidelines.
noted that parenteral infusion risk with low molecular weight aspx. Rotigotine was found to improve RLS symptom severity iron dextran is lower (1 per 200,000)105 than that with high according to IRLS by 7.0 (95% CI: 5.6 to 8.4)107-111; the results molecular weight iron dextran. Additionally, parenteral iron are shown in Figure 12. Other outcomes measures including therapy with iron sucrose, iron gluconate or ferumoxytol car- PSG-measured PLMI and PLM arousal index,111 RLS severity ries no anaphylactic risk.106 (RLS-6),108,109 CGI-I,107-110 and QoL107,109 also improved signifi- cantly. Figure 13 shows the evidence profile.
4.2.5a: Clinicians may use supplemental iron to treat RLS
Two long-term continuation studies were reported, Oertel et patients with low ferritin levels. (OPTION)
al.112 (220 patients for 1 year) and Hogl et al.113 (190 patients for 2 Values and Trade-Offs: RLS therapy with iron may be ef-
years). The IRLS total score improved by −17.4 ± 9.9 points be- fective in patients with RLS associated with low ferritin levels. tween baseline and end of year 1 (P < 0.001) and by −15.4 ± 10.3 Parenteral high molecular weight iron dextran therapy carries for the 2-year study. The other measures of symptom severity, the potential for anaphylactic reaction. The parenteral infusion sleep satisfaction, and QoL supported the efficacy of rotigotine.
risk with low molecular weight iron dextran is substantially Doses ranged from 1107 to 4.5 mg,108 with increasing effec- lower. Moreover, parenteral iron therapy with iron sucrose, iron tiveness up to approximately 3 mg/d. Oertel et al.112 reported gluconate, or ferumoxytol carries no anaphylactic risk. Howev- the mean daily dose after 1 year was 2.8 ± 1.2 mg/24 h with 4 er, whenever possible, oral iron replacement is recommended. mg/24 h (40.6%) being the most frequently applied dose. Braun Oral supplemental iron carries fewer side effects—primarily et al.114 concluded from their pharmacokinetic interaction data constipation and rare cases of iron overload.
that rotigotine dose adjustment would not be needed if dom- peridone was added to the treatment regimen. In 2008, this drug 4.3 Therapies For Which No Recommendations Are Made
was withdrawn from the U.S. market because of concerns about The following section contains information on those phar- inconsistent absorption from the patch.
macological and nonpharmacological RLS therapies for which The transdermal patch was safe and generally well tolerated a recommendation level could not be given secondary to either by the majority of patients. Oertel et al.112 reported after 1 year insufficient evidence to support any recommendation or be- of study that the tolerability was described as ‘ good" or ‘ very cause the therapy is no longer available in the U.S.
good" by 80.3% of all patients. Side effects were mostly mild to SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al moderate, including application site reactions (40%112−43%109), Although clonazepam received an OPTION level of recom- nausea (9.5%112), and fatigue (6.4%112). Hogl et al.113 reported at a mendation in 1999 as described in the evidence review, ben- median dose of 4 mg/d that 87% of patients experienced at least zodiazepines lack clinical data necessary to assess efficacy in 1 adverse event, the majority of which were mild or moderate, treating RLS. The committee strongly recommends that alter- but 22% of these were severe. Additionally, the most frequent nate and better studied RLS medications be considered in RLS adverse event in year 2 was any application site disorder (16.4%), therapy. The "no recommendation" status applies to the use of followed by 4.5% with back pain and 4.1% with nasopharyngitis. benzodiazepines as a first line agent. For example, clonazepam Transdermal rotigotine was withdrawn from the market because could still be considered as an adjunctive medication in treat- of drug crystallization that resulted in suboptimal absorption.
ment of RLS.
4.3.2 Other dopaminergic medications: lisuride and amantadine
4.3.5 Valproic acid
There is insufficient evidence at this time to support the use There is insufficient evidence at present to evaluate the use of lisuride in the treatment of RLS, and it is not FDA-approved. of valproic acid for RLS. A single, small RCT by Eisensehr et Two small studies by Benes et al.,115,116 1 a non-randomized al.123 reported no major difference between the efficacy of val- treatment trial116 and the other a randomized controlled trial,115 proic acid (VPA) and levodopa on 20 patients with moderate- reported on the effect of lisuride on patients with severe and/or to-severe idiopathic RLS. Follow-up 6 to 18 months after the advanced RLS. The non-randomized treatment trial116 of 20 pa- study end revealed that VPA was still effective in 75% (9 of 12 tients reported that lisuride given orally as a monotherapy (0.3 patients), whereas only 29% (2 of 7 patients) were still satis- mg) as well as in conjunction with L-dopa (150 mg) significant- fied with levodopa (P = 0.048). The authors conclude that slow- ly improved CGI-I and PLM index. The randomized controlled release VPA provides an alternative or adjunctive treatment for trial115 of 10 patients reported that lisuride transdermal patches patients unable to tolerate dopaminergics or those suffering significantly improved RLS-6, CGI-I, PLM index (actigraphy), from augmentation, and not as a first-line treatment for RLS. and IRLS (−23.5 with lisuride and −10.6 with placebo). Side In 2009, the FDA issued a warning that there is an increased effects were typical for dopaminergic drugs. With the excep- risk of neural tube defects and other major birth defects, such tion of nausea and dizziness in one patient, none of the adverse as craniofacial defects and cardiovascular malformations, in ba- events were rated as severe.
bies exposed to valproate sodium and related products (valproic No new studies were found on amantadine since the previous acid and divalproex sodium) during pregnancy.
practice parameter, which reported that in 1 clinical series (Evi- dente et al.117) of 21 patients, half the patients benefited acutely by amantadine as an add-on medication, with long-term benefit There is insufficient evidence at present to evaluate the use in a minority. In 2004, the strength of this recommendation was of valerian for RLS. In one RCT by Cuellar and Ratcliffe on 48 OPTION level. However, currently no recommendation has patients,124 it was reported that although PSQI, ESS, and IRLS been given for amantadine as several superior options are avail- all decreased, no significant differences were found between able; there was limited existing evidence, and no new evidence placebo and 800 mg/d valerian. In patients with ESS > 10, va- for the use of amantadine in RLS.
lerian significantly improved symptoms of RLS and decreased daytime sleepiness. Higher doses should be considered in fu- 4.3.3 Other dopamine agonists
ture studies.
There is insufficient evidence at this time to support the use of talipexole, peribedil, and alpha-dihydroergocryptine in the 4.3.7 Avoidance of antidepressants
treatment of RLS. In the previous practice parameter (2004), The evidence on the issue of whether or not antidepressant these agents were given an OPTION level of recommendation use can cause or exacerbate RLS symptoms is conflicting. Three based on very low level evidence (1 small case series for each studies were identified that reported there is an association be- drug), one of which (Inoue, talipexole) would not have been tween antidepressants and the occurrence of RLS. Baughman et accepted in this paper because there were only 5 patients, 2 of al.125 interviewed 1693 veterans and reported on the relationship whom had uremia.
between antidepressants and gender. Men were found to have an increased risk of developing RLS with antidepressant use, 4.3.4 Benzodiazepines (clonazepam)
RR = 1.77 (95% CI 1.26, 2.48), whereas for women, there was There is insufficient information on the effect of benzodiaz- no increased risk—RR = 0.79 (0.43, 1.47). For men, the high- epines on the treatment of RLS. In addition to 3 studies118-120 dis- est odds ratios were found for citalopram, paroxetine, and ami- cussed in the last review, 2118,119 of which were RCTs with small tryptiline. One antidepressant, fluoxetine, was found to show an numbers of patients (n = 6) and showed contradictory results, increased odds ratio for women (RR = 2.47 [1.33, 4.56]). Kim 1 non-randomized treatment trial on 10 patients with RLS by et al.126 performed a retrospective chart review of 181 charts and Saletu et al.121 reported that 1 mg clonazepam improved objec- found that 8% of patients who were treated with mirtazapine tive sleep efficiency and subjective sleep quality but did not developed RLS symptoms, typically within a few days after reduce the PLM index. The authors concluded that clonazepam introduction of the drug. A higher odds ratio was found with had an acute therapeutic effect on insomnia, which is a different the concomitant use of tramadol and dopamine-blocking agents. mode of action than dopamine agonists. An additional paper122 Lastly, Rottach et al.127 studied second-generation antidepres- suggested that clonazepam was not as effective as pramipexole sants in a prospective observational study of 271 participants. in the treatment of RLS.
Nine percent of patients developed RLS as a side effect with the SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al use of these second generation antidepressants with the excep- tom severity relief, improvement of general health, body pain, tion of reboxetine. Twenty-eight percent of mirtazapine users re- social functions, and sleep parameters according to the IRLS ported RLS. In another investigation, 243 subjects with affective rating scale, SF-36, and PSQI. Sloand et al.136 reported in an and anxiety disorders were studied systematically for the emer- RCT on 25 patients that 4 weeks of 1000 mg IV iron dextran
gence of symptoms of RLS after antidepressant use. In contrast during dialysis resulted in significant, but transient, reduction to the previously discussed studies, in this study antidepressants in symptoms of RLS in patients with ESRD according to an were not found to be a major risk factor for RLS.128 Further- author-developed questionnaire. Pellecchia et al.137 reported in more, Brown et al.129 reported the results of a retrospective chart an unblinded RCT on the effects of 6 weeks each of ropinirole
review of 200 consecutive patients presenting with insomnia. (mean dosage 1.45 mg/d) versus sustained-release levodopa There were no statistically significant associations between RLS (mean dosage 190 mg/d) in 10 patients on chronic hemodialy- and antidepressant use or any specific class of antidepressant.
sis with RLS. Ropinirole resulted in a significantly higher im- provement (73.5% vs. 33.5%) in IRLS scores, sleep time, and 4.3.8 Non-pharmacological therapy
PGI. No adverse events were reported during ropinirole treat- There is insufficient evidence at present to evaluate the use of ment. Mirada et al.138 reported in a nonrandomized treatment non-pharmacological therapy for RLS, including accommodative trial on the effects of 0.125-0.75 mg of pramipexole on 10 pa-
strategies, sleep hygiene, behavioral and stimulation therapies, tients with RLS that was severe enough to interfere with their compression devices, exercise, and nutritional considerations. dialysis treatment such that they required disconnection. At a No studies were found on accommodative strategies, sleep mean follow-up time of 8 months, the IRLS and PLMI were hygiene, or nutritional considerations since the last review. significantly reduced, whereas differences in sleep latency, to- Regarding cognitive behavioral therapy, one non-randomized, tal hours of sleep, number of awakenings, and sleep efficiency non-blinded treatment trial (Hornyak et al.130) reported that were not statistically significant. Lastly, 2 small studies (14139 IRLS, QoL-RLS, and mental health status (SCL-90-R) scores and 18140 patients) showed promising results of the effect of improved significantly through 3 months with 8 weekly 90-min exercise on IRLS139 and PLM during hemodialysis140 in hemo-
sessions in group therapy consisting of mindfulness-based ex- dialysis patients.
ercises, stress-reduction strategies, diary-based analysis, and Other information from the 1999 review paper2 includes: medical education.
"Dialysis itself does not appear to alter the RLS or PLMD Lettieri and Eliasson131 (RCT) and Eliasson and Lettieri132 secondary to end-stage renal disease, but the dialysate tem-
(non-randomized, non-blinded treatment trial) reported that perature may influence symptoms.141 Erythropoietin supple-
wearing compression devices a minimum of 1 h per day for mentation may reduce symptoms, and symptoms often largely 1 to 3 months was significantly superior to sham treatment on resolve with kidney transplantation as reported in a case re-
IRLS, JHRLSS, RLS-QoL, ESS, and the Fatigue Visual Analog port and abstract.142,143 Two clinical trials meeting study criteria Scale; furthermore, one-third of patients experienced complete included patients with end-stage renal disease and found effica- resolution of symptoms. The authors suggested that these de- cy for levodopa.144,145 One did not.146 One trial98 with clonidine
vices may be potential adjunctive or alternative therapies for revealed efficacy in this group of patients. Some case reports RLS patients.
suggest efficacy for benzodiazepines (clonazepam).147 Ne-
One small (11 therapy and 12 controls) unblinded RCT by phrologists, noting that carbidopa is a pyridoxine (B6) inhibi- Aukerman et al.133 reported that 12 weeks of exercise therapy tor, suggest providing an additional daily B6 supplement of 10 (aerobic and lower-body resistance training for 3 days/week) mg.148 In considering other potential medications for dialysis significantly decreased RLS symptoms (IRLS rating scale and patients, the elimination patterns of the medications and their an ordinal RLS scale) versus the control group. The exercise active metabolites need to be considered (e.g., gabapentin is program was shown to be an effective treatment to improve the dialyzable, whereas meperidine, propoxyphene, valproic acid symptoms of RLS.
and carbamazepine are not148)." Neuropathy—In a nonrandomized treatment trial, Sommer
4.3.9 Secondary RLS and special patient groups
et al.149 reported on the effect of pregabalin on 16 patients with There is insufficient evidence on the effectiveness of any one secondary RLS, most with neuropathy and neuropathic pain therapy or the balance of benefits to harm in the treatment of and 3 with idiopathic RLS. The final mean daily dose was 305 ± secondary RLS, children, pregnant women, or other special pa- 185 mg. All patients self-rated a satisfactory or good alleviation tient groups for a recommendation to be made. of RLS symptoms and maintained pregabalin, 5 with additional End Stage Renal Disease (ESRD)—Six studies discussed
medication, for a mean duration of 217 ± 183 days.
the treatment of patients with ESRD and/or those on hemodi- Superficial venous insufficiency (SVI)—A study by Hayes et
alysis who also had RLS. Various treatments were used in the al.150 reported that RLS symptoms were alleviated in 18 treatment studies. The first was an RCT by Thorp et al.,134 who reported subjects but not in 15 controls who all had concurrent moderate- that 200-300 mg gabapentin after each hemodialysis session
to-very severe RLS (IRLS rating scale ≥ 15) and duplex-proven on 13 patients significantly improved RLS symptoms according SVI. The treatment consisted of endovenous laser ablation of to an author-developed questionnaire based on the IRLS rating refluxing superficial axial veins and ultrasound-guided sclero- scale. A small (14 patients) unblinded RCT by Micozkadioglu therapy of the associated varicose veins with post-operative ACE et al.135 compared the effects of 200 mg/d gabapentin versus
wrap for 48 h followed by compression stockings for 2 weeks. 125 mg/d L-dopa on hemodialysis patients. They reported that The mean IRLS score decreased significantly by 21.4 points gabapentin was significantly superior to L-dopa on RLS symp- from 26.9 to 5.5 for treatment subjects, whereas control scores SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al did not decrease. Fifty-three percent of patients had a 6-week fol- sleep was unchanged, and non-significant reductions in the low-up score ≤ 5, and 31% had a follow-up score of 0, indicating number of PLMs per hour of sleep and in the percentage of a complete relief of RLS symptoms. The 1999 review included arousals associated with PLMs were observed.
the results of an unblinded study151 on 113 selected patients with documented SVI and complaints of RLS. After 1-10 treatments of intravenous sclerotherapy with sodium tetradecyl sulfate, 98% In the 2004 practice parameters, 1 study (Grewal et al.,154 a of patients reported notable improvement in RLS symptoms, al- case series on 31 patients) was discussed where selegiline was though 28% of these relapsed by the 2-year follow up.
used successfully to treat PLMD. No new studies were found on selegiline.
5.0 THERAPIES FOR PLMD
Periodic limb movements of sleep (PLMS) are frequently 5.0a: There is insufficient evidence at present to comment on
seen as an incidental finding during sleep studies. In some the use of pharmacological therapy in patients diagnosed with
cases in which there are frequent PLMS and a subjective per- PLMD alone. (NO RECOMMENDATION)
ception of poor sleep in the absence of RLS or sleep-related Values and Trade Offs: There is insufficient evidence to
breathing disorder, PLMD can be diagnosed.6 Although there comment on pharmacologic therapies in isolated PLMD. Ex- are no studies of dopaminergic treatment of PLMD, many of isting data in RLS therapy does, in some cases, support some the studies of dopaminergic medication effects on RLS looked medical interventions in both RLS and PLMD. Clinical judg- at PLMS and periodic limb movements during wakefulness ment must be used in any pharmacologic intervention in PLMD.
(PLMW). Some studies demonstrated statistically signifi- cant falls in PLM indices with Stalevo,60 pramipexole,35,41,42,45 6.0 CONCLUSIONS AND FUTURE DIRECTIONS
ropinorole,49,52,53 and rotigotine.111 In addition, gabapentin90,91 Since the prior practice parameter, a considerable amount and pregabalin93 were also shown to decrease PLM indices in of literature has been published on the effects of dopaminergic subjects with RLS. Thus, although there were no studies on medications for RLS. However, there were a significant number the efficacy of these medications in a population with PLMD, of therapies, both pharmacological and nonpharmacological, they have been noted to decrease PLM indices in subjects with that received "no recommendation" due to the dearth of infor- RLS and might be effective in treating the sleep dysfunction mation regarding their use in the setting of RLS. Furthermore, of PLMD. The following sections review medications tried in there is a paucity of data comparing medications in head-to- subjects with PLMD.
head trials to determine their relative effectiveness and adverse event profiles. For this reason, and the fact that therapy should always be tailored to the individual, a dopaminergic "drug of In a nonrandomized treatment trial, Saletu et al.121 discussed choice" cannot be recommended. It is worth noting that the late the acute effects of 1 mg clonazepam (1 night each of trial drug development of augmentation (even after one year of continu- and placebo) on idiopathic PLMD. Clonazepam significantly ous therapy on dopaminergic agents) remains a significant con- improved objective sleep efficiency and subjective sleep qual- cern, and patients need to be monitored throughout therapy for ity, PLM during time in bed, PLM during REM, and PLM dur- this particular side effect.
ing wake-time, but did not reduce the PLM index. The authors Additionally, Godau et al.155 have noted that the RLS treat- concluded that clonazepam had an acute therapeutic effect on ment successes that have been demonstrated in pharmacological insomnia rather than limb movements.
trials have not been consistently replicated in the clinical set- ting. The authors suggest that this could be related to the fact that approximately two-thirds of the patients with idiopathic In a 6-week open clinical trial on 9 patients, Kunz et al.152 RLS evaluated in clinical practice are excluded from pharma- reported that 3 mg of melatonin taken 30 min prior to bedtime cological trials secondary to the presence of neuropsychiatric significantly improved the movement parameters associated comorbidities. These comorbidities include anxiety, depression, with PLMD (4 severe [PLM index > 50], 3 moderate [PLM chronic pain, and various somatoform disorders. A possible way index 26-50], and 2 mild [PLM index 5 thru 25]). Melatonin to circumvent this limitation is to include cognitive behavioral improved Zerssen well-being (a self-rating mood scale) in 7 of therapies or psychotherapy as part of the treatment regimens. the 9 patients; significantly reduced PLMs, PLM index, PLMs Investigations including patients with both RLS and neuropsy- with arousals and PLM-arousal index; and significantly reduced chiatric comorbidities would be more clinically germane.
movement rate and minutes with movements during time in bed Finally, randomized controlled trials evaluating treatment as measured by actigraphy.
options for patients with secondary RLS and PLMD are lack- ing. Multiple medications that can be considered for idiopathic RLS do not have sufficient evidence in the setting of second- In a nonrandomized treatment trial, Ehrenberg et al.153 re- ary RLS or PLMD to warrant a recommendation level. These ported on the effects of low-dose valproate (125-600 mg at practice parameters highlight the need for further investigations bedtime) on 6 patients with PLMD for a mean of 6 months of assessing treatments for secondary RLS and PLMD.
treatment. All patients experienced statistically significant im- provement in subjective daytime alertness and objective sleep parameters including sleep efficiency (76% to 88%), stage 1 Estimate of effect: The observed relationship between an sleep (26% to 13%), stage 3 and 4 sleep (19% to 30%). REM intervention and an outcome expressed as, for example, a SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al number needed to treat, odds ratio, risk difference, risk ra- 19. Fulda S, Wetter T. Where dopamine meets opioids: a meta-analysis of tio, relative risk reduction, standardized mean difference, or the placebo effect in restless legs syndrome treatment studies. Brain weighted mean difference. 20. Cornelius JR, Tippmann-Peikert M, Slocumb NL, Frerichs CF, Silber MH. Impulse control disorders with the use of dopaminergic agents in restless legs syndrome: a case-control study. Sleep 2010;33:81-7.
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IRLS rating scale total scores for cabergoline, treatment vs. baseline
IRLS Baseline
IRLS Cabergoline
Study Length
# Pts Completed
Dose, mg/d
Stiasny-Kolster, 200464 †Number of patients on 2 mg dose, out of 85 patients in complete dose-finding trial. *Back calculated from difference data. **After 1 week of placebo treatment (24.3 ± 2.9 at baseline). tx, treatment.
IRLS rating scale total scores for cabergoline vs. placebo
Study Length /
# Pts Completed
Dose, mg/d
IRLS Comparison Avg (SD)
IRLS Cabergoline Avg (SD) P
Cabergoline vs. placebo
5 wks / 40 (20 each tx) Stiasny-Kolster, 200464 5 wks / 44 (22 each tx) Cabergoline vs. levodopa
Trenkwalder, 200767 2-3 cabergoline -8.8 ± 10.7 tx, treatment.
Appendix continues on the following page SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al Appendix (continued)—Data for meta-analyses
IRLS rating scale total scores for pramipexole
Dose quoted, IRLS Baseline
Pramipexole
Study Length / # Pts Completed
Large studies with placebo control
12 weeks / 199 placebo, 203 pramipexole Placebo: 25.8 ± 5.4 Pramipexole: 25.9 ± 5.2 Ferini-Strambi, 12 weeks / ITT 179 placebo, Placebo: 24.6 ± 5.7 178 pramipexole (278 completed) Pramipexole: 24.2 ± 5.2 6 weeks / 115 placebo, 230 pramipexole Placebo: 24.9 ± 5.4 Pramipexole: 24.7 ± 5.2 12 weeks / 86 placebo, 80 pramipexole Placebo: 23.5 ± 5.2 (281 total completed all doses) Pramipexole: 22.9 ± 5.1 Large study without placebo control
6 weeks / 154 divided into 3 dose groups -12.3‡ [95% CI: Not Small studies with placebo control
6 weeks / 21 placebo, 20 pramipexole Placebo: 25.1 ± 5.8 Pramipexole: 23.4 ± 6.4 3 weeks / 21 placebo, 22 pramipexole 0.5 mg (0.125 Placebo: 22.9 ± 4.2 to 0.75 tested) Pramipexole: 23.6 ± 3.7 3 weeks / 22 each pramipexole 0.5 mg Placebo: 22.9 ± 4.2 and placebo (107 total completed all Pramipexole: 23.6 ± 3.7 Long-term trial data
*Calculated from 0.125 mg for 15.4% (28/182), 0.25 mg for 33.0% (60/182), 0.5 mg for 26.9% (49/182), and 0.75 mg for 24.7% (45/182). **Median dose. †Calculated from SE data given. ‡Mean of all doses.
Appendix continues on the following page SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al Appendix (continued)—Data for meta-analyses
IRLS rating scale total scores for ropinirole
Study Length /
IRLS Placebo IRLS Ropinirole
# Pts Completed
Dose, mg/d
IRLS Baseline Avg (SD)
4 wks each / 22 each tx 2 wks / 13 placebo, 9 12 wks / 186 ropinirole, 191 2.1 ± 1.2 Ropinirole: 22.0 ± 5.0 Placebo: 21.6 ± 4.8 12 wks / 146 ropinirole, 138 1.9 ± 1.1 Ropinirole: 24.4 ± 5.75 Placebo: 25.2 ± 5.63 12 wks / 102 ropinirole, 107 1.5 Ropinirole: 23.6 ± 5.9 Placebo: 24.8 ± 5.4 Other data not used in meta-analysis
Garcia-Borreguero, 1 year / 233 OC and 307 Not applicable 10.9 ± 7.71 12 wks / 175 ropinirole, 184 3.1 ± 2.0 Montplaisir, 200655 12 wks / 92 Baseline = 24 weeks treated Adjusted treatment difference in favor of ropinirole at week 12 *Estimated from figure in paper, SD calculated from graph data. OC, observed case; LOCF, Last observation carried forward. IRLS rating scale total scores for rotigotine
Study Length /
IRLS Placebo
IRLS Rotigotine
# Pts Completed
Dose,* mg/d
6 mo / 99 placebo, Placebo: 23.1 ± 5.1 Rotigotine: 23.6 ± 5.0 4 wks / 20 placebo, Placebo: 25.4 ± 6.3 Rotigotine: 26.3 ± 6.4 6 wks / 333 total-53 Placebo: 28.0 ± 6.3 placebo, 64 rotigotine Rotigotine:: 27.4 ± 6.1 Stiasny-Kolster, 1 wk / 62 total-14 Placebo: 25.0 ± 18.7 placebo,19 rotigotine Rotigotine: 25.9 ± 23.5 6 mo / 114 placebo, Placebo: 28.1 ± 6.3 Rotigotine: 28.0 ± 5.9 *Data for other doses are listed in the evidence table available online at http://www.aasmnet.org/practiceguidelines.aspx.
Appendix continues on the following page SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al Appendix (continued)—Data for meta-analyses
IRLS rating scale total scores for gabapentin enacarbil (GEn)
Study Length /
IRLS Placebo
IRLS Gabapentin
# Pts Completed
IRLS Baseline Avg (SD)
Enacarbil Avg (SD)
12 wks / 92 placebo, Placebo: 22.6 ± 4.9 2 wks / 24 each treatment 2 wks / 33 placebo, 33 Gen Placebo: 22.4 ± 4.6 Ellenbogan 201188 52 wks / 376 in safety -15.2 ± 8.85 LOCF 12 wks / 77/97 placebo, Placebo: 23.8 ± 4.58 GEn: 23.1 ± 4.93 12 wks / 77/97 placebo, Placebo: 23.8 ± 4.58 GEn: 23.2 ± 5.32 *Data for other doses are reported in the paper.
SLEEP, Vol. 35, No. 8, 2012 Treatment of RLS and PLMD in Adults: 2012 Update—Aurora et al

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Management of acute and chronic migraine Gianluca Cand Jean Sc Purpose of reviewWe highlight the recent clinical trials for the management of acute and chronic migraine. Recent findingsIn women with menstrual migraine, triptans seem to be well tolerated irrespective of whether or not patientsare taking oestrogen-containing contraceptives or have comorbidities that indicate increased cardiovascularrisk. The new acute drug, telcagepant, a calcitonin gene-related peptide (CGRP) antagonist, is safe forlong-term use (up to 18 months) in migraine patients with stable coronary artery disease in whom the useof triptans is not advisable. From the pooled analysis of the two Phase III Research Evaluating MigraineProphylaxis Therapy studies of onabotulinumtoxinA (BOTOX) in chronic migraineurs, it clearly emerged thatefficacy increases overtime (up to 56 weeks) and paralleled self-perceived improvement in quality of life.Effectiveness was also observed in patients with severely disabling headaches, who met criteria for triptanabuse and were refractory to several prophylactic treatments. Finally, combination of preventivepharmacological agents with different action mechanisms may be the next frontier in therapeuticadvancements for treating migraine.

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Ari Brynjolfsson: Time Dilation and Supernovas Ia Plasma Redshift, Time Dilation, and Supernovas Ia Ari Brynjolfsson ∗ Applied Radiation Industries, 7 Bridle Path, Wayland, MA 01778, USA The measurements of the absolute magnitudes and redshifts of supernovas Ia show that con- ventional physics, which includes plasma redshift, fully explains the observed magnitude-redshiftrelation of the supernovas. The only parameter that is required is the Hubble constant, whichin principle can be measured independently. The contemporary theory of the expansion of theuniverse (Big Bang) requires in addition to the Hubble constant several adjustable parameters,such as an initial explosion, the dark matter parameter, and a time adjustable dark energyparameter for explaining the supernova Ia data. The contemporary Big Bang theory also re-quires time dilation of distant events as an inherent premise. The contention is usually that thelight curves of distant supernovas show or even prove the time dilation. In the present article,we challenge this assertion. We document and show that the previously reported data in factindicate that there is no time dilation. The data reported by Riess et al. in the AstrophysicalJournal in June 2004 confirm the plasma redshift, the absence of time dilation, dark matter,and dark energy.