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-Analyses: An American Academy of Sleep Medicine Clinical Practice Guideline

Overall, dopaminergic agents are the most extensively investigated and used therapies for the treatment of RLS. Since the prior practice parameter update, the literature has advanced considerably with regards to both the number and quality of studies for dopaminergic treatment of RLS. While these agents confer many benefits, there are some adverse effects that should be recognized. Similar to patients with Parkinson's disease, RLS patients treated with dopamine agonists may develop dopamine dysregulation syndrome.^20-25 These patients may exhibit an addictive pattern of dopamine replacement therapy use and/or behavioral disturbances including punding and impulse control disorders such as pathologic gambling, compulsive shopping, compulsive eating, and hypersexuality. One report²⁰ indicated a prevalence of 7% for pathologic gambling and 23% for compulsive eating in RLS subjects treated with a dopaminergic medication. Case reports indicate that discontinuation of the dopamine agonist results in resolution or improvement of the impulse control disorder,^26-28 although these patients may be particularly susceptible to dopamine agonist withdrawal syndrome.²⁹ The levodopa review encompassed an aggregate of medications with varying dopa decarboxylase inhibitor types (DDCI).

Opioids are effective in the treatment of RLS, especially for patients with RLS that is not relieved by other treatments. (Level of evidence: Low) In addition to 2 small RCTs that studied oxycodone and propoxyphene discussed in the 1999 review,^76,77 3 new studies (1 open-label and 2 retrospective reviews) were found on the effects of opioids on RLS.^78-80 Lauerma and Markkula⁷⁸ reported that 10 of 12 patients found tramadol to be more effective than drugs they had tried in the past, 1 experienced some relief, and 1 had no relief. Some patients alternated tramadol with levodopa or clonazepam while other patients took “drug holidays” or used it intermittently to minimize concerns of abuse. There is one report of augmentation with long-term tramadol treatment.⁸¹ In a retrospective review of 113 patients on long-term (up to 5 years) opioid therapy (most commonly tilidine, dihydrocodeine, codeine, propoxyphene, or methadone), Walters et al.⁷⁹ reported that opioids seem to have long-term effectiveness in the treatment of RLS and PLMS, but patients on long-term opioid therapy should be clinically or polysomnographically monitored periodically for the development of sleep apnea, as 3 of 7 subjects developed worsening sleep apnea. Lastly, Ondo⁸⁰ reported on the effect of methadone (5-40 mg/day) in 29 patients who had failed dopaminergics. Sixty-three percent of the patients remained on methadone for 23 ± 12 months, all of whom reported at least a 75% reduction in symptoms and no augmentation. Silver et al.⁴⁷ reported no augmentation leading to the end of treatment with methadone in a 10-year retrospective review of 76 patients on methadone. The median daily dose after 8-10 years on methadone treatment was no more than 10 mg greater than at 6 months, indicating minimal change in narcotic requirement over time.

Values and Trade-Offs: Opioid data shows clinical effectiveness in treating RLS with a low level of evidence. As mentioned above, side effects can include an undefined potential for abuse in predisposed patients and a possible risk for the development or worsening of sleep apnea. Therefore, patients should be clinically monitored for the development of symptoms. In general, however, this medication is very well tolerated and has a lower risk of augmentation than is seen in the dopaminergic medications.

Clonidine is effective in the treatment of RLS (Level of evidence: Low). No new evidence was found on the use of clonidine since the last complete review² where there were 2 small studies of 11⁹⁷ and 20⁹⁸ patients. The studies were also short-term (3 days⁹⁸ to 2-3 weeks⁹⁷). Both were double-blind and placebo controlled, but randomization was unclear in one.⁹⁸ Because of these limitations and other considerations, the data using the current methodology is considered low. The results of Wagner et al.,⁹⁷ as reported by Hening et al.,² are that “clonidine resulted in significant improvement compared to baseline in subjective measures and sleep latency, though PLMI was not significantly decreased. There was no correlation between plasma clonidine concentration and control of symptoms. Side effects were frequent (8 of 10 patients); however, no patients left the study due to them.” Side effects were generally considered mild, and included dry mouth, decreased cognition, lightheadedness, sleepiness post dose, constipation, decreased libido, and headache. Ausserwinkler and Schmidt⁹⁸ reported that “clonidine significantly improved RLS symptoms, with 8/10 patients having complete relief of symptoms.”

Values and Trade-Offs: Clonidine has minimal supporting data in treating RLS and carries a considerable risk for side effects. Clonidine might be considered in treating hypertension and RLS concomitantly. The risk of side effects (such as hypotension in normotensive patients) associated with clonidine in the treatment of RLS makes the benefit-to-harm ratio unclear.

Iron supplementation has not been shown to be effective in the treatment of RLS, except perhaps in patients with iron deficiency or refractory RLS. (Level of evidence: Very low)

There were 6 studies in total on 3 forms of iron treatment: oral iron sulfate, IV iron sucrose, and IV iron dextran. Overall, the data are conflicting, but show some improvement in select cases, typically those with low serum ferritin levels. Davis et al.⁹⁹ and Wang et al.¹⁰⁰ studied oral iron sulfate. Davis et al. reported no significant effect on quality after 12 weeks. Wang et al. also examined the use of oral iron sulfate. In an RCT with 18 patients with low serum ferritin levels, the investigators showed a statistically significant improvement in IRLS with 2 doses of 325 mg/d. Earley et al.¹⁰¹ and Grote et al.¹⁰² assessed 1000 mg iron sucrose administered in 2 doses of 500 mg or 5 doses of 200 mg. Earley et al. stopped the trial early (after 2 weeks) because of no effect demonstrated on the global rating scale and PLMS. Grote et al. reported on patients with variable degrees of iron deficiency at several lengths of follow up including 2 months and 12 months. There was no statistically different change in IRLS observed at either endpoint. The dropouts for lack of treatment effect were higher in the placebo group (61% vs. 17%). The use of IV iron dextran for treatment of RLS has also been examined. Earley et al.¹⁰³ and Ondo¹⁰⁴ investigated IV iron dextran. The study by Earley et al. consisted of 11 patients and was open-label. Results were mixed. Ondo reported on 25 subjects in a retrospective review of severe refractory RLS. It was demonstrated that iron dextran can dramatically improve refractory RLS, but results were inconsistent and not predicted by patient demographics. Anaphylactic symptoms are a risk. In 2009, the FDA issued a warning that analphylactic-type reactions, including fatalities, have followed the parenteral administration of iron dextran injection. The boxed warning recommends administering a test dose prior to the first therapeutic dose and observing reactions. However, it should be noted that parenteral infusion risk with low molecular weight iron dextran is lower (1 per 200,000)¹⁰⁵ than that with high molecular weight iron dextran. Additionally, parenteral iron therapy with iron sucrose, iron gluconate or ferumoxytol carries no anaphylactic risk.¹⁰⁶

Values and Trade-Offs: RLS therapy with iron may be effective in patients with RLS associated with low ferritin levels. Parenteral high molecular weight iron dextran therapy carries the potential for anaphylactic reaction. The parenteral infusion risk with low molecular weight iron dextran is substantially lower. Moreover, parenteral iron therapy with iron sucrose, iron gluconate, or ferumoxytol carries no anaphylactic risk. However, whenever possible, oral iron replacement is recommended. Oral supplemental iron carries fewer side effects—primarily constipation and rare cases of iron overload.

Rotigotine as a transdermal patch is effective in the treatment of moderate-to-severe RLS, but was withdrawn from the U.S. in 2008 (Level of evidence: High). This is a new treatment since the last review, and the evidence base is 5 studies^107-111 for the meta-analysis. No limitations were noted with the studies, and the results were consistent. All data are presented in the online supplement at http://www.aasmnet.org/practiceguidelines.aspx. Rotigotine was found to improve RLS symptom severity according to IRLS by 7.0 (95% CI: 5.6 to 8.4)^107-111; the results are shown in Figure 12. Other outcomes measures including PSG-measured PLMI and PLM arousal index,¹¹¹ RLS severity (RLS-6),^108,109 CGI-I,^107-110 and QoL^107,109 also improved significantly. Figure 13 shows the evidence profile.

Two long-term continuation studies were reported, Oertel et al.¹¹² (220 patients for 1 year) and Hogl et al.¹¹³ (190 patients for 2 years). The IRLS total score improved by −17.4 ± 9.9 points between baseline and end of year 1 (P < 0.001) and by −15.4 ± 10.3 for the 2-year study. The other measures of symptom severity, sleep satisfaction, and QoL supported the efficacy of rotigotine.

Doses ranged from 1¹⁰⁷ to 4.5 mg,¹⁰⁸ with increasing effectiveness up to approximately 3 mg/d. Oertel et al.¹¹² reported the mean daily dose after 1 year was 2.8 ± 1.2 mg/24 h with 4 mg/24 h (40.6%) being the most frequently applied dose. Braun et al.¹¹⁴ concluded from their pharmacokinetic interaction data that rotigotine dose adjustment would not be needed if domperidone was added to the treatment regimen. In 2008, this drug was withdrawn from the U.S. market because of concerns about inconsistent absorption from the patch.

The transdermal patch was safe and generally well tolerated by the majority of patients. Oertel et al.¹¹² reported after 1 year of study that the tolerability was described as “good” or “very good” by 80.3% of all patients. Side effects were mostly mild to moderate, including application site reactions (40%¹¹²−43%¹⁰⁹), nausea (9.5%¹¹²), and fatigue (6.4%¹¹²). Hogl et al.¹¹³ reported at a median dose of 4 mg/d that 87% of patients experienced at least 1 adverse event, the majority of which were mild or moderate, but 22% of these were severe. Additionally, the most frequent adverse event in year 2 was any application site disorder (16.4%), followed by 4.5% with back pain and 4.1% with nasopharyngitis. Transdermal rotigotine was withdrawn from the market because of drug crystallization that resulted in suboptimal absorption.

There is insufficient evidence at this time to support the use of lisuride in the treatment of RLS, and it is not FDA-approved. Two small studies by Benes et al.,^115,116 1 a non-randomized treatment trial¹¹⁶ and the other a randomized controlled trial,¹¹⁵ reported on the effect of lisuride on patients with severe and/or advanced RLS. The non-randomized treatment trial¹¹⁶ of 20 patients reported that lisuride given orally as a monotherapy (0.3 mg) as well as in conjunction with L-dopa (150 mg) significantly improved CGI-I and PLM index. The randomized controlled trial¹¹⁵ of 10 patients reported that lisuride transdermal patches significantly improved RLS-6, CGI-I, PLM index (actigraphy), and IRLS (−23.5 with lisuride and −10.6 with placebo). Side effects were typical for dopaminergic drugs. With the exception of nausea and dizziness in one patient, none of the adverse events were rated as severe.

No new studies were found on amantadine since the previous practice parameter, which reported that in 1 clinical series (Evidente et al.¹¹⁷) of 21 patients, half the patients benefited acutely by amantadine as an add-on medication, with long-term benefit in a minority. In 2004, the strength of this recommendation was OPTION level. However, currently no recommendation has been given for amantadine as several superior options are available; there was limited existing evidence, and no new evidence for the use of amantadine in RLS.

There is insufficient evidence at this time to support the use of talipexole, peribedil, and alpha-dihydroergocryptine in the treatment of RLS. In the previous practice parameter (2004), these agents were given an OPTION level of recommendation based on very low level evidence (1 small case series for each drug), one of which (Inoue, talipexole) would not have been accepted in this paper because there were only 5 patients, 2 of whom had uremia.

There is insufficient information on the effect of benzodiazepines on the treatment of RLS. In addition to 3 studies^118–120 discussed in the last review, 2^118,119 of which were RCTs with small numbers of patients (n = 6) and showed contradictory results, 1 non-randomized treatment trial on 10 patients with RLS by Saletu et al.¹²¹ reported that 1 mg clonazepam improved objective sleep efficiency and subjective sleep quality but did not reduce the PLM index. The authors concluded that clonazepam had an acute therapeutic effect on insomnia, which is a different mode of action than dopamine agonists. An additional paper¹²² suggested that clonazepam was not as effective as pramipexole in the treatment of RLS.

Although clonazepam received an OPTION level of recommendation in 1999 as described in the evidence review, benzodiazepines lack clinical data necessary to assess efficacy in treating RLS. The committee strongly recommends that alternate and better studied RLS medications be considered in RLS therapy. The “no recommendation” status applies to the use of benzodiazepines as a first line agent. For example, clonazepam could still be considered as an adjunctive medication in treatment of RLS.

There is insufficient evidence at present to evaluate the use of valproic acid for RLS. A single, small RCT by Eisensehr et al.¹²³ reported no major difference between the efficacy of valproic acid (VPA) and levodopa on 20 patients with moderate-to-severe idiopathic RLS. Follow-up 6 to 18 months after the study end revealed that VPA was still effective in 75% (9 of 12 patients), whereas only 29% (2 of 7 patients) were still satisfied with levodopa (P = 0.048). The authors conclude that slow-release VPA provides an alternative or adjunctive treatment for patients unable to tolerate dopaminergics or those suffering from augmentation, and not as a first-line treatment for RLS. In 2009, the FDA issued a warning that there is an increased risk of neural tube defects and other major birth defects, such as craniofacial defects and cardiovascular malformations, in babies exposed to valproate sodium and related products (valproic acid and divalproex sodium) during pregnancy.

There is insufficient evidence at present to evaluate the use of valerian for RLS. In one RCT by Cuellar and Ratcliffe on 48 patients,¹²⁴ it was reported that although PSQI, ESS, and IRLS all decreased, no significant differences were found between placebo and 800 mg/d valerian. In patients with ESS > 10, valerian significantly improved symptoms of RLS and decreased daytime sleepiness. Higher doses should be considered in future studies.

The evidence on the issue of whether or not antidepressant use can cause or exacerbate RLS symptoms is conflicting. Three studies were identified that reported there is an association between antidepressants and the occurrence of RLS. Baughman et al.¹²⁵ interviewed 1693 veterans and reported on the relationship between antidepressants and gender. Men were found to have an increased risk of developing RLS with antidepressant use, RR = 1.77 (95% CI 1.26, 2.48), whereas for women, there was no increased risk—RR = 0.79 (0.43, 1.47). For men, the highest odds ratios were found for citalopram, paroxetine, and amitryptiline. One antidepressant, fluoxetine, was found to show an increased odds ratio for women (RR = 2.47 [1.33, 4.56]). Kim et al.¹²⁶ performed a retrospective chart review of 181 charts and found that 8% of patients who were treated with mirtazapine developed RLS symptoms, typically within a few days after introduction of the drug. A higher odds ratio was found with the concomitant use of tramadol and dopamine-blocking agents. Lastly, Rottach et al.¹²⁷ studied second-generation antidepressants in a prospective observational study of 271 participants. Nine percent of patients developed RLS as a side effect with the use of these second generation antidepressants with the exception of reboxetine. Twenty-eight percent of mirtazapine users reported RLS. In another investigation, 243 subjects with affective and anxiety disorders were studied systematically for the emergence of symptoms of RLS after antidepressant use. In contrast to the previously discussed studies, in this study antidepressants were not found to be a major risk factor for RLS.¹²⁸ Furthermore, Brown et al.¹²⁹ reported the results of a retrospective chart review of 200 consecutive patients presenting with insomnia. There were no statistically significant associations between RLS and antidepressant use or any specific class of antidepressant.

No studies were found on accommodative strategies, sleep hygiene, or nutritional considerations since the last review. Regarding cognitive behavioral therapy, one non-randomized, non-blinded treatment trial (Hornyak et al.¹³⁰) reported that IRLS, QoL-RLS, and mental health status (SCL-90-R) scores improved significantly through 3 months with 8 weekly 90-min sessions in group therapy consisting of mindfulness-based exercises, stress-reduction strategies, diary-based analysis, and medical education.

Lettieri and Eliasson¹³¹ (RCT) and Eliasson and Lettieri¹³² (non-randomized, non-blinded treatment trial) reported that wearing compression devices a minimum of 1 h per day for 1 to 3 months was significantly superior to sham treatment on IRLS, JHRLSS, RLS-QoL, ESS, and the Fatigue Visual Analog Scale; furthermore, one-third of patients experienced complete resolution of symptoms. The authors suggested that these devices may be potential adjunctive or alternative therapies for RLS patients.

One small (11 therapy and 12 controls) unblinded RCT by Aukerman et al.¹³³ reported that 12 weeks of exercise therapy (aerobic and lower-body resistance training for 3 days/week) significantly decreased RLS symptoms (IRLS rating scale and an ordinal RLS scale) versus the control group. The exercise program was shown to be an effective treatment to improve the symptoms of RLS.

End Stage Renal Disease (ESRD)—Six studies discussed the treatment of patients with ESRD and/or those on hemodialysis who also had RLS. Various treatments were used in the studies. The first was an RCT by Thorp et al.,¹³⁴ who reported that 200-300 mg gabapentin after each hemodialysis session on 13 patients significantly improved RLS symptoms according to an author-developed questionnaire based on the IRLS rating scale. A small (14 patients) unblinded RCT by Micozkadioglu et al.¹³⁵ compared the effects of 200 mg/d gabapentin versus 125 mg/d L-dopa on hemodialysis patients. They reported that gabapentin was significantly superior to L-dopa on RLS symptom severity relief, improvement of general health, body pain, social functions, and sleep parameters according to the IRLS rating scale, SF-36, and PSQI. Sloand et al.¹³⁶ reported in an RCT on 25 patients that 4 weeks of 1000 mg IV iron dextran during dialysis resulted in significant, but transient, reduction in symptoms of RLS in patients with ESRD according to an author-developed questionnaire. Pellecchia et al.¹³⁷ reported in an unblinded RCT on the effects of 6 weeks each of ropinirole (mean dosage 1.45 mg/d) versus sustained-release levodopa (mean dosage 190 mg/d) in 10 patients on chronic hemodialysis with RLS. Ropinirole resulted in a significantly higher improvement (73.5% vs. 33.5%) in IRLS scores, sleep time, and PGI. No adverse events were reported during ropinirole treatment. Mirada et al.¹³⁸ reported in a nonrandomized treatment trial on the effects of 0.125-0.75 mg of pramipexole on 10 patients with RLS that was severe enough to interfere with their dialysis treatment such that they required disconnection. At a mean follow-up time of 8 months, the IRLS and PLMI were significantly reduced, whereas differences in sleep latency, total hours of sleep, number of awakenings, and sleep efficiency were not statistically significant. Lastly, 2 small studies (14¹³⁹ and 18¹⁴⁰ patients) showed promising results of the effect of exercise on IRLS¹³⁹ and PLM during hemodialysis¹⁴⁰ in hemodialysis patients.

Other information from the 1999 review paper² includes: “Dialysis itself does not appear to alter the RLS or PLMD secondary to end-stage renal disease, but the dialysate temperature may influence symptoms.¹⁴¹ Erythropoietin supplementation may reduce symptoms, and symptoms often largely resolve with kidney transplantation as reported in a case report and abstract.^142,143 Two clinical trials meeting study criteria included patients with end-stage renal disease and found efficacy for levodopa.^144,145 One did not.¹⁴⁶ One trial⁹⁸ with clonidine revealed efficacy in this group of patients. Some case reports suggest efficacy for benzodiazepines (clonazepam).¹⁴⁷ Nephrologists, noting that carbidopa is a pyridoxine (B6) inhibitor, suggest providing an additional daily B6 supplement of 10 mg.¹⁴⁸ In considering other potential medications for dialysis patients, the elimination patterns of the medications and their active metabolites need to be considered (e.g., gabapentin is dialyzable, whereas meperidine, propoxyphene, valproic acid and carbamazepine are not¹⁴⁸).”

Neuropathy—In a nonrandomized treatment trial, Sommer et al.¹⁴⁹ reported on the effect of pregabalin on 16 patients with secondary RLS, most with neuropathy and neuropathic pain and 3 with idiopathic RLS. The final mean daily dose was 305 ± 185 mg. All patients self-rated a satisfactory or good alleviation of RLS symptoms and maintained pregabalin, 5 with additional medication, for a mean duration of 217 ± 183 days.

Superficial venous insufficiency (SVI)—A study by Hayes et al.¹⁵⁰ reported that RLS symptoms were alleviated in 18 treatment subjects but not in 15 controls who all had concurrent moderate-to-very severe RLS (IRLS rating scale ≥ 15) and duplex-proven SVI. The treatment consisted of endovenous laser ablation of refluxing superficial axial veins and ultrasound-guided sclerotherapy of the associated varicose veins with post-operative ACE wrap for 48 h followed by compression stockings for 2 weeks. The mean IRLS score decreased significantly by 21.4 points from 26.9 to 5.5 for treatment subjects, whereas control scores did not decrease. Fifty-three percent of patients had a 6-week follow-up score ≤ 5, and 31% had a follow-up score of 0, indicating a complete relief of RLS symptoms. The 1999 review included 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% of patients reported notable improvement in RLS symptoms, although 28% of these relapsed by the 2-year follow up.