Adjunctive tonic motor activation enables opioid reduction for refractory restless legs syndrome: a prospective, open-label, single-arm clinical trial.

BACKGROUND: There is a large population of restless legs syndrome (RLS) patients who are refractory to medication. Whereas experts recommend off-label opioids as an effective long-term treatment for refractory RLS, reducing opioid dose could substantially reduce side effects and risks. Tonic motor activation (TOMAC) is a nonpharmacological therapeutic device indicated for refractory RLS. Here, we investigated if TOMAC could enable opioid dose reduction for refractory RLS. METHODS: This prospective, open-label, single-arm clinical trial [NCT04698343] enrolled 20 adults taking ≤ 60 morphine milligram equivalents (MMEs) per day for refractory RLS. Participants self-administered 30-min TOMAC sessions bilaterally over the peroneal nerve when RLS symptoms presented. During TOMAC treatment, opioid dose was reduced iteratively every 2-3 weeks until Clinician Global Impression of Improvement (CGI-I) score relative to baseline exceeded 5. Primary endpoint was percent of participants who successfully reduced opioid dose ≥ 20% with CGI-I ≤ 5. Secondary endpoints included mean successful percent opioid dose reduction with CGI-I ≤ 5. RESULTS: On average, participants were refractory to 3.2 medications (SD 1.6) and were taking a stable dose of opioids for 5.3 years (SD 3.9). Seventy percent of participants (70%, 14 of 20) successfully reduced opioid dose ≥ 20% with CGI-I ≤ 5. Mean percent opioid dose reduction with CGI-I ≤ 5 was 29.9% (SD 23.7%, n = 20) from 39.0 to 26.8 MME per day. Mean CGI-I score at the reduced dose was 4.0 (SD 1.4), indicating no change to RLS severity. CONCLUSIONS: For refractory RLS, TOMAC enabled substantial opioid dose reduction without increased RLS symptoms. These results suggest that TOMAC has the potential to reduce the risk profile associated with opioid therapy for refractory RLS. TRIAL REGISTRATION: ClinicalTrials.gov trial number NCT04698343 registered on January 6, 2021.

Bilateral high-frequency noninvasive peroneal nerve stimulation evokes tonic leg muscle activation for sleep-compatible reduction of restless legs syndrome symptoms.

STUDY OBJECTIVES: Restless legs syndrome (RLS) is a prevalent sleep disorder with limited treatment options. Bilateral high-frequency noninvasive peroneal nerve stimulation (NPNS) reduces RLS symptoms. Here, we sought to characterize the mechanism of action for NPNS and identify predictors of treatment response. We hypothesized that, similar to voluntary leg movements, NPNS reduces RLS symptoms by activating leg muscles. METHODS: For 20 adults with moderate-severe RLS, we tested this hypothesis by recording surface electromyography (EMG) from the tibialis anterior leg muscle while administering NPNS at varying amplitudes to determine the minimum NPNS amplitude that evoked EMG activity (motor threshold) and maximal NPNS amplitude that was not distracting (therapeutic intensity level). Afterwards, participants self-administered NPNS (at the therapeutic intensity level) and sham control for 14 days, each in randomized order. Efficacy was defined as International RLS Study Group Rating Scale (IRLS) score difference for NPNS compared with sham. RESULTS: NPNS consistently activated leg muscles; NPNS evoked EMG activity at the therapeutic intensity level for 19 of 20 participants (mean TIL: 26.6 mA, mean MT: 18.3 mA). Evoked EMG activity was tonic (not phasic) and sustained over time. Evoked EMG activity predicted efficacy; participants with lower motor thresholds had greater IRLS improvement (r = .45, P = .046). NPNS treatment did not interfere with self-reported sleep onset (NPNS: 16% of nights; sham: 11%; P = .629) and frequently improved self-reported sleep onset (NPNS: 52% of nights; sham: 15%; P = .002). CONCLUSIONS: These results demonstrate that NPNS reduces RLS symptoms by activating afferent pathways, thereby generating tonic and sustained leg muscle activity without interfering with sleep. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Noninvasive Peripheral Nerve Stimulation for Restless Legs Syndrome; URL: https://clinicaltrials.gov/ct2/show/NCT04700683; Identifier: NCT04700683. CITATION: Charlesworth JD, Adlou B, Singh H, Buchfuhrer MJ. Bilateral high-frequency noninvasive peroneal nerve stimulation evokes tonic leg muscle activation for sleep-compatible reduction of restless legs syndrome symptoms. J Clin Sleep Med. 2023;19(7):1199-1209.

The Management of Restless Legs Syndrome: An Updated Algorithm.

Restless legs syndrome (RLS) is a common disorder. The population prevalence is 1.5% to 2.7% in a subgroup of patients having more severe RLS with symptoms occurring 2 or more times a week and causing at least moderate distress. It is important for primary care physicians to be familiar with the disorder and its management. Much has changed in the management of RLS since our previous revised algorithm was published in 2013. This updated algorithm was written by members of the Scientific and Medical Advisory Board of the RLS Foundation based on scientific evidence and expert opinion. A literature search was performed using PubMed identifying all articles on RLS from 2012 to 2020. The management of RLS is considered under the following headings: General Considerations; Intermittent RLS; Chronic Persistent RLS; Refractory RLS; Special Circumstances; and Alternative, Investigative, and Potential Future Therapies. Nonpharmacologic approaches, including mental alerting activities, avoidance of substances or medications that may exacerbate RLS, and oral and intravenous iron supplementation, are outlined. The choice of an alpha2-delta ligand as first-line therapy for chronic persistent RLS with dopamine agonists as a second-line option is explained. We discuss the available drugs, the factors determining which to use, and their adverse effects. We define refractory RLS and describe management approaches, including combination therapy and the use of high-potency opioids. Treatment of RLS in pregnancy and childhood is discussed.

Noninvasive neuromodulation reduces symptoms of restless legs syndrome.

STUDY OBJECTIVES: Restless legs syndrome (RLS) is a common neurological disorder characterized by an uncontrollable nocturnal urge to move the legs and often associated with chronic sleep disturbances. The most common treatments for RLS are medications that can have debilitating side effects. Here, we evaluated a novel alternative modality of RLS treatment, noninvasive bilateral electrical stimulation of the common peroneal nerve. METHODS: To assess the impact of this noninvasive peripheral nerve stimulation (NPNS) approach to RLS symptomatology, we conducted a multisite randomized crossover study comparing NPNS to sham. RLS patients with moderate-to-severe RLS (n = 37) self-administered NPNS and sham nightly for 14 days per treatment in randomized order. RESULTS: NPNS resulted in a reduction in RLS severity of 6.81 points on the International RLS Rating Scale relative to 3.38 for sham (P < .01) and a 66% clinically significant responder rate on the Clinical Global Impressions-Improvement scale compared to 17% for sham (P < .01). Subgroup analysis indicated that medication-resistant and medication-naïve participants both exhibited similarly robust responses. There were no moderate or serious device-related adverse events. CONCLUSIONS: These results suggest that NPNS could be a promising alternative to pharmacological therapies for RLS and could provide a solution for medication-resistant RLS patients and for medication-naïve RLS patients who are unwilling or unable to take medication. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Noninvasive Peripheral Nerve Stimulation for Restless Legs Syndrome; URL: https://clinicaltrials.gov/ct2/show/NCT04700683; Identifier: NCT04700683. CITATION: Buchfuhrer MJ, Baker FC, Haramandeep S, et al. Noninvasive neuromodulation reduces symptoms of restless legs syndrome. J Clin Sleep Med. 2021;17(8):1685-1694.

Validation of the self-administered version of the international Restless Legs Syndrome study group severity rating scale - The sIRLS.

INTRODUCTION: The International Restless Legs Study Group (IRLSSG) has developed the IRLS (International Restless Legs Syndrome Severity Scale) and validated it as a clinician/researcher administered scale to be used when both patient and examiner are present. The IRLSSG recognized the need for a self-completing scale that can be used economically in clinical practice and in large population-based studies. In this study the validity and the reliability of the IRLS as a self-administered scale (sIRLS) is assessed. METHODS: Established RLS patients were recruited by eight centers in four countries and consented to participate in this study. The validity of the sIRLS was assessed by patients completing the sIRLS before a clinician administered the IRLS. The reliability of the sIRLS was assessed by patients completing the sIRLS again, two weeks after the first one, provided no change had occurred. RESULTS: Overall, 173 patients were recruited and 164 of them were included in the analyses. The sIRLS showed satisfactory scaling assumptions and no relevant floor or ceiling effect. One factor explained 61.3% of the variance. Cronbach's alpha was 0.93 and the item homogeneity index was 0.59. Intraclass correlation coefficient between the sIRLS and the IRLS was 0.94. The sIRLS standard error of measurement was 3.61 (½ SD at baseline = 4.11). The results mostly overlapped those of the IRLS analyzed in parallel. DISCUSSION: The sIRLS is a reliable, valid and precise instrument that showed tight association with the IRLS. These findings support the use of the sIRLS for self-evaluation of RLS severity. The responses obtained on the sIRLS and the IRLS scale varied slightly. Therefore, we recommend that either the sIRLS or the IRLS scale be used as the only scale for serial measures over time.

Restless legs syndrome (RLS) with expansion of symptoms to the face.

BACKGROUND: It has been well established that restless legs syndrome (RLS) manifests with symptoms most frequently in the legs followed by the arms. Other body parts may be affected but it has been somewhat controversial as to whether symptoms may extend to the face. METHODS: We are reporting two cases of RLS showing unusual extension of symptoms. RESULTS: These two patients presented with symptoms which extended to body parts beyond the legs, including to the face. The facial symptoms can be relieved by walking, massage or medication. CONCLUSION: It is important to be aware of unusual extension of symptoms either as progression of the disease or as manifestation of augmentation.

The Appropriate Use of Opioids in the Treatment of Refractory Restless Legs Syndrome.

Restless legs syndrome (RLS) is a distinct disorder, differing from chronic pain in many ways. Refractory RLS is characterized by unresponsiveness to dopamine agonists or alpha-2-delta ligands due to inadequate efficacy, augmentation, or adverse effects. This may result in severely impaired quality of life, profound insomnia, and suicidal depression. Opioid therapy is a mainstay in the management of these patients. This article summarizes the basic science and clinical evidence in support of their use, including the positive result of a large controlled multicenter study of 306 subjects, and outlines an approach to their use in clinical practice. Treatable explanations for RLS refractoriness, such as low iron stores, and other therapeutic options, such as combination therapy, should be considered before prescribing opioids. The agents most commonly used are oxycodone and methadone, but tramadol, codeine, morphine, and hydrocodone can also be considered. Controlled-release medication should be used for evening dosage and short-acting drugs, if needed, during the day. Effective doses are considerably lower than used for chronic pain (oxycodone 10-30 mg daily; methadone 5-20 mg daily) and the risk of opioid use disorder is relatively low. However, sensible precautions should be undertaken, including assessing opioid risk with standard questionnaires, using an opioid contract, using urine drug screens, consulting state prescription drug monitoring programs, and frequent reevaluation of effectiveness and side effects. Opioid use in selected patients with refractory RLS may be life-transforming with favorable risk-benefit ratio.

The Effect of Gabapentin Enacarbil on Pain Associated with Moderate-to-Severe Primary Restless Legs Syndrome in Adults: Pooled Analyses from Three Randomized Controlled Trials.

BACKGROUND: Adults with moderate-to-severe primary restless legs syndrome (RLS) often experience painful dysesthesias, which may lead to impaired quality of life. OBJECTIVES: The aim of this study was to assess the effects of gabapentin enacarbil (GEn) on pain associated with moderate-to-severe primary RLS in adults. METHODS: Data were pooled from three double-blind, randomized, placebo-controlled, 12-week trials (NCT00298623, NCT00365352, NCT01332305) for adults receiving GEn or placebo once daily. Change in average daily RLS pain score and a combined International Restless Legs Scale (IRLS)-pain response were examined. RESULTS: The modified intention-to-treat population included 671 adults (placebo, n = 244; GEn 600 mg, n = 161; GEn 1200 mg, n = 266). Both GEn doses significantly improved average daily RLS pain score at week 12 (p < 0.001 for GEn 600 mg vs. placebo and GEn 1200 mg vs. placebo). The combined IRLS-pain response subanalysis included 366 patients with a baseline IRLS total score ≥15 and pain score ≥4 (placebo, n = 133; GEn 600 mg, n = 86; GEn 1200 mg, n = 147). Most patients were both IRLS and pain responders (placebo, 40 %; GEn 600 mg, 70 %; GEn 1200 mg, 67 %). Spearman rank correlations between IRLS total and pain score (change from baseline to week 12) were moderate or strong. The most frequent treatment-emergent adverse events were somnolence (placebo, 5 %; GEn 600 mg, 20 %; GEn 1200 mg, 23 %) and dizziness (placebo, 4 %; GEn 600 mg, 13 %; GEn 1200 mg, 22 %). CONCLUSIONS: This post hoc pooled analysis suggests that GEn (600 and 1200 mg) once daily significantly improved pain associated with moderate-to-severe primary RLS in adults; however, the analysis was not powered to detect statistical differences between the two GEn doses. Numerically, more GEn-treated patients had a combined IRLS-pain response than placebo-treated patients.

Efficacy of gabapentin enacarbil in adult patients with severe primary restless legs syndrome.

AIM: Assess efficacy and tolerability of gabapentin enacarbil (GEn) in adults with severe primary restless legs syndrome (RLS). METHODS: We pooled data from three 12-week, double-blind, placebo-controlled, randomized trials (NCT00298623, NCT00365352, NCT01332305) across GEn 600-mg, GEn 1200-mg, and placebo treatment groups for severe primary RLS (baseline International Restless Legs Scale (IRLS) total score ≥24). Co-primary end points at week 12 were mean change from baseline in IRLS total score and proportion of responders ("much"/very much" improved) on the investigator-rated Clinical Global Impression - Improvement (CGI-I) Scale. Outcomes for individual IRLS items (eg, sleep, mood, quality of life, pain, safety) were assessed. RESULTS: A total of 309 patients had severe primary RLS (placebo, n = 110; GEn 600 mg, n = 80; GEn 1200 mg, n = 119). GEn 600 mg and 1200 mg significantly improved least-squares mean IRLS total scores versus placebo at week 12 (placebo, -12.3; GEn 600 mg, -16.3; GEn 1200 mg, -18.0; treatment difference vs. placebo, both p <0.01). Significantly more patients with severe primary RLS treated with GEn 600 mg (64%) and 1200 mg (74%) were CGI-I responders at week 12 versus placebo (42%; p <0.01 for both GEn doses). Both GEn doses led to significant improvements in the other outcomes explored versus placebo at week 12. The most frequent treatment-emergent adverse events (TEAEs) were somnolence (GEn, 21-24%; placebo, 3%) and dizziness (GEn, 14-19%; placebo, 3%). CONCLUSIONS: GEn (600 mg or 1200 mg) once daily significantly improved RLS symptoms and consequences of these symptoms in severe primary RLS. The most frequent TEAEs were somnolence and dizziness.

Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation.

A Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) in conjunction with the European Restless Legs Syndrome Study Group (EURLSSG) and the RLS Foundation (RLS-F) to develop evidence-based and consensus-based recommendations for the prevention and treatment of long-term pharmacologic treatment of dopaminergic-induced augmentation in restless legs syndrome/Willis-Ekbom disease (RLS/WED). The Task Force made the following prevention and treatment recommendations: As a means to prevent augmentation, medications such as α2δ ligands may be considered for initial RLS/WED treatment; these drugs are effective and have little risk of augmentation. Alternatively, if dopaminergic drugs are elected as initial treatment, then the daily dose should be as low as possible and not exceed that recommended for RLS/WED treatment. However, the physician should be aware that even low dose dopaminergics can cause augmentation. Patients with low iron stores should be given appropriate iron supplementation. Daily treatment by either medication should start only when symptoms have a significant impact on quality of life in terms of frequency and severity; intermittent treatment might be considered in intermediate cases. Treatment of existing augmentation should be initiated, where possible, with the elimination/correction of extrinsic exacerbating factors (iron levels, antidepressants, antihistamines, etc.). In cases of mild augmentation, dopamine agonist therapy can be continued by dividing or advancing the dose, or increasing the dose if there are breakthrough night-time symptoms. Alternatively, the patient can be switched to an α2δ ligand or rotigotine. For severe augmentation the patient can be switched either to an α2δ ligand or rotigotine, noting that rotigotine may also produce augmentation at higher doses with long-term use. In more severe cases of augmentation an opioid may be considered, bypassing α2δ ligands and rotigotine.

Treatment response to sleep, pain, and mood disturbance and their correlation with sleep disturbance in adult patients with moderate-to-severe primary restless legs syndrome: Pooled analyses from 3 trials of gabapentin enacarbil.

INTRODUCTION: This pooled analysis investigated the effects of gabapentin enacarbil (GEn) on clinical correlates of sleep disturbance in adults with moderate-to-severe primary restless legs syndrome (RLS) and no-to-moderate or severe-to-very severe baseline sleep disturbance. METHODS: Co-primary end-points were mean change from baseline to week 12 in International Restless Legs Scale (IRLS) total score and proportion of responders ('much'/'very much' improved) on the investigator-rated Clinical Global Impression-Improvement (CGI-I) scale (week 12). Pain, mood, individual IRLS items, and safety were assessed. RESULTS: The modified intent-to-treat population was 671 adults randomized to GEn 600 mg (n = 161), GEn 1200 mg (n = 266), or placebo (n = 244). GEn significantly improved least squares mean change in IRLS total score from baseline versus placebo for no-to-moderate (GEn 600 mg,- 12.3; 1200 mg, - 11.3; placebo, - 7.7) and severe-to-very severe (- 16.6; - 17.0; - 12.7) groups (all P < 0.01). Significantly more GEn-treated patients (both doses) were CGI-I responders (week 12) versus placebo in both sleep subgroups (all P < 0.01). GEn substantially improved mood and pain scores for both sleep subgroups versus placebo. The most frequent treatment-emergent adverse events were somnolence and dizziness. CONCLUSION: GEn (600 mg and 1200 mg) was effective and well tolerated in adults with moderate-to-severe primary RLS regardless of baseline sleep disturbance level.

An algorithm for the management of restless legs syndrome.

Restless legs syndrome (RLS) is a common disorder with a prevalence of 5% to 15%. Primary care physicians must become familiar with management of this disorder. This algorithm for the management of RLS was written by members of the Medical Advisory Board of the Restless Legs Syndrome Foundation and is based on scientific evidence and expert opinion. Restless legs syndrome is divided into intermittent, daily, and refractory types. Nonpharmacological approaches, including mental alerting activities, avoiding substances or medications that may exacerbate RLS, and addressing the possibility of iron deficiency, are discussed. The role of carbidopa/levodopa, dopamine agonists, opioids, benzodiazepines, and anticonvulsants for the different types of the disorder is delineated.

Strategies for the treatment of restless legs syndrome.

Restless legs syndrome (RLS) is a common neurological disorder of unknown etiology that is managed by therapy directed at relieving its symptoms. Treatment of patients with milder symptoms that occur intermittently may be treated with nonpharmacological therapy but when not successful, drug therapy should be chosen based on the timing of the symptoms and the needs of the patient. Patients with moderate to severe RLS typically require daily medication to control their symptoms. Although the dopamine agonists, ropinirole and pramipexole have been the drugs of choice for patients with moderate to severe RLS, drug emergent problems like augmentation may limit their use for long term therapy. Keeping the dopamine agonist dose as low as possible, using longer acting dopamine agonists such as the rotigotine patch and maintaining a high serum ferritin level may help prevent the development of augmentation. The α2δ anticonvulsants may now also be considered as drugs of choice for moderate to severe RLS patients. Opioids should be considered for RLS patients, especially for those who have failed other therapies since they are very effective for severe cases. When monitored appropriately, they can be very safe and durable for long term therapy. They should also be strongly considered for treating patients with augmentation as they are very effective for relieving the worsening symptoms that occur when decreasing or eliminating dopamine agonists.