A comprehensive update on the ADMET considerations for α2δ calcium channel ligand medications for treating restless legs syndrome.

INTRODUCTION: Restless legs syndrome/Willis-Ekbom disease (RLS/WED) is a sleep-related sensory-motor disorder associated with poor sleep quality and impaired daily functioning. In patients affected by chronic RLS/WED, a pharmacological therapy is recommended. International guidelines suggest to start the treatment with a α2δ calcium channel ligand in most cases, unless contraindicated. AREAS COVERED: The present review is based on an extensive Internet and PubMed search from 1986 to 2024. Our purpose is to describe the absorption, distribution, metabolism, and toxicology (ADMET) of the α2δ ligands, with common consideration for the therapeutic class, specificities of different compounds, efficacy, and safety in relation to other treatment options. EXPERT OPINION: α2δ ligands are quite similar in their ADMET profiles, sharing most of the pharmacokinetics and potential adverse effects. However, we highlight the linear kinetic of gabapentin enacarbil and pregabalin, differently from gabapentin. α2δ ligands are safe and effective for the treatment of RLS/WED. Additional benefits can be obtained in comorbid insomnia, chronic pain syndromes, history of impulse control disorder, and comorbid anxiety. The use of α2δ ligands is associated with poor risk of augmentation. We still need new long-term safe and effective treatments, which could be developed along with our knowledge of RLS/WED pathophysiology.

Restless Legs Syndrome in Children and Adolescents.

Children with psychiatric comorbidities frequently are referred for evaluation of sleep complaints. Common sleep symptoms can include difficulty falling asleep, frequent nocturnal awakening, restless sleep, and symptoms of restless legs syndrome (RLS). The understanding of the sleep condition in relation to the psychiatric comorbidity often is a challenge to the physician and often sleep disorders remain undiagnosed, untreated, or undertreated. Restless legs syndrome has been associated with psychiatric comorbidities and with certain medications, such as antidepressants, antihistamines, and antipsychotics. This article reviews the presentation of RLS and restless sleep, the association with psychiatric comorbidities, and treatment options.

Treatment of Sleep, Motor and Sensory Symptoms with the Orexin Antagonist Suvorexant in Adults with Idiopathic Restless Legs Syndrome: A Randomized Double-Blind Crossover Proof-of-Concept Study.

BACKGROUND AND OBJECTIVES: Current treatment guidelines for restless legs syndrome (RLS) recommend treatment be initiated with non-dopaminergic drugs. Given the potential role of orexins in the pathophysiology of RLS, we performed a pilot, proof-of-concept study to investigate the therapeutic effects of suvorexant, a dual orexin receptor antagonist (DORA), on sleep and sensory/motor symptoms in individuals with idiopathic RLS. METHODS: This was a randomized, double-blind, crossover and placebo-controlled study. Inclusion criteria were diagnosis with idiopathic RLS, an International RLS Study Group Severity Rating Scale (IRLS) score > 15, and the absence of significant RLS symptoms before 9 pm. Following washout from any previous central nervous system (CNS)-active drugs, patients were randomized to receive either suvorexant or placebo for two consecutive 2-week treatment periods. Treatment was administered at 9 pm at a fixed dose of 10 mg/day during the first week, and 20 mg during the second week. Primary and coprimary endpoints were wake after sleep onset (WASO) and total sleep time (TST), respectively, while IRLS rating scale score, multiple suggested immobilization tests (m-SIT), and periodic limb movements (PLMs) were secondary endpoints. RLS severity was measured weekly using the IRLS and Clinical Global Improvement (CGI) scales. m-SIT were also performed between 8 pm and midnight at the end of each treatment phase and were followed by a sleep study. RESULTS: A total of 41 participants were randomized, 40 of whom completed the study. Compared with placebo, treatment with suvorexant significantly improved RLS symptoms (according to IRLS total score, CGI, and the m-SIT), PLM during sleep, and PLM with arousal. Improvement of RLS symptoms was greater in those who had not been exposed to dopaminergic agents in the past. Sleep architecture also improved with significant changes in TST, WASO, sleep onset latency, sleep efficiency, non rapid-eye movement stage 1 (N1) %, non rapid-eye movement stage 2 (N2) %, and rapid eye movement (REM) %. Suvorexant was well tolerated in RLS, with few and mild adverse events. CONCLUSIONS: Our results provide the first proof of evidence of the therapeutic efficacy of DORAs in improving sleep and sensory and motor symptoms in RLS. Given orexin's role in pain and sensory processing, potential mechanisms of action are discussed. CLASSIFICATION OF EVIDENCE: The study provides class II evidence supporting the therapeutic efficacy of suvorexant in patients with RLS with sleep disturbance. TRIAL REGISTRATION: EudraCT#: 2017-004580-12.

Chronic dizziness in restless legs syndrome (RLS) patients responsive to levodopa or dopamine agonists.

Apart from the legs, restless legs syndrome (RLS) also affects the arms, head, neck, face, oral cavity, genital area, abdomen, intestines and bladder. RLS is also linked to several comorbid diseases, including headache disorders. Its association with dizziness has never been explored. We are reporting on two patients with RLS who also had a history of chronic dizziness. The treatment with levodopa or dopamine agonists completely alleviated both RLS and dizziness. We propose that RLS-like symptoms in the head may be experienced as dizziness and that dizziness may be part of the symptom complex of RLS. A large number of patients with chronic dizziness remain undiagnosed in clinical practice. We suggest exploring the history of RLS in patients presenting with chronic dizziness. Such patients may respond to levodopa or dopamine agonists. Because the response was seen in only two patients, a prospective placebo-controlled trial is needed to confirm these findings.

Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome.

Restless legs syndrome (RLS) is responsive to opioid, dopaminergic and iron-based treatments. Receptor blocker studies in RLS patients suggest that the therapeutic efficacy of opioids is specific to the opioid receptor and mediated indirectly through the dopaminergic system. An RLS autopsy study reveals decreases in endogenous opioids, ß-endorphin and perhaps Met-enkephalin in the thalamus of RLS patients. A total opioid receptor knock-out (mu, delta and kappa) and a mu-opioid receptor knock-out mouse model of RLS show circadian motor changes akin to RLS and, although both models show sensory changes, the mu-opioid receptor knock mouse shows circadian sensory changes closest to those seen in idiopathic RLS. Both models show changes in striatal dopamine, anaemia and low serum iron. However, only in the total receptor knock-out mouse do we see the decreases in serum ferritin that are normally found in RLS. There are also decreases in serum iron when wild-type mice are administered a mu-opioid receptor blocker. In addition, the mu-opioid receptor knock-out mouse also shows increases in striatal zinc paralleling similar changes in RLS. Adrenocorticotropic hormone and α-melanocyte stimulating hormone are derived from pro-opiomelanocortin as is ß-endorphin. However, they cause RLS-like symptoms and periodic limb movements when injected intraventricularly into rats. These results collectively suggest that an endogenous opioid deficiency is pathogenetic to RLS and that an altered melanocortin system may be causal to RLS as well.

Treatment of primary restless legs syndrome with Fu's subcutaneous needling: A case report.

RATIONALE: Fu's subcutaneous needling (FSN) is a novel acupuncture technique developed based on traditional needling principles that aims to alleviate diseases by improving local muscle conditions and blood supply. FSN have been widely used for the treatment of various diseases. Restless legs syndrome (RLS) is a common central nervous system disorder characterized by intense discomfort in the legs, particularly at night, leading to an urge to move the legs for relief. In this study, we report a case in which FSN was used to treat primary RLS. PATIENT CONCERNS: A 67-year-old patient complained of nocturnal discomfort in the right leg for over 4 months, the symptoms occurred 2-3 times, with uncontrollable movement impulses in the right leg during the onset, accompanied by a burning sensation, lasting about 2 h, accompanied by anxiety and insomnia. Imaging examinations revealed no spinal stenosis or history of kidney disease, rheumatic disease, diabetes, or Parkinson's disease. DIAGNOSES: The patient was diagnosed with primary RLS, and the International Restless Legs Syndrome Study Group rating scale (IRLS) score was 26. INTERVENTIONS: FSN was successfully performed three times per week on different days. No adverse and unanticipated events while the treatment. The total treatment course lasted for six weeks. OUTCOMES: After the treatment, the patient reported that the recent onset interval was approximately 10 days, each time lasting approximately 15 min. The patient's IRLS score was 5, After a follow-up of 2 months following the end of treatment, the patient reported that the incidence of RLS was approximately one episode within two weeks,each lasting approximately 10 min. LESSONS: FSN significantly improved leg discomfort and desire for leg movement in patients with RLS. FSN may exert its therapeutic effects by influencing connective and muscular tissues, thereby improving the condition of the central nervous system and the local blood supply in the legs. However, due to the limitation of a single clinical observation case, a randomized clinical trial with a sufficient follow-up time is needed.

Perceptions of exercise and restless legs syndrome: Results from a nationwide survey.

Restless legs syndrome is a prevalent, sensorimotor sleep disorder temporarily relieved by movement, with evidence of symptomatic improvement with regular exercise. The present study describes perceptions of the effects of exercise on symptoms of restless legs syndrome. Participants (N = 528) completed a mixed-methods (i.e. numerical and narrative), nationwide survey including items assessing personal experiences with exercise and restless legs syndrome (both positive and negative), as well as restless legs syndrome diagnosis, restless legs syndrome severity, and demographic and clinical characteristics. Responses varied widely on specific experiences with exercise, but a higher percentage of participants indicated positive experiences with exercise than those who reported negative experiences (72%-40%, respectively) with exercise. Further, 54% of respondents reported that exercise only improves restless legs syndrome, while 24% reported exercise only worsens symptoms. Participants described that any abrupt change in exercise routine would almost always elicit restless legs syndrome symptoms (e.g. hiking for a long time, stopping an exercise routine), and that a consistent pattern of exercise improved restless legs syndrome symptoms with an overall beneficial effect on the frequency of symptomatic bouts. Participants further described time of day as impactful for their exercise experience, with > 50% indicating morning exercise improves symptoms and evening exercise worsens symptoms. Participants described several questions that they wanted answered regarding the evidence for exercise in restless legs syndrome and specific exercise prescription recommendations. The present study describes information crucial to the creation of stakeholder-informed health promotion programs for individuals with restless legs syndrome to optimize personalized treatment plans that could prevent and manage symptoms.

Can restless legs be a sign of something else? A case report of spondyloarthritis presenting with restless legs syndrome and a review of the literature.

Restless legs syndrome (RLS) is a chronic movement disorder characterized by an urge or need to move the limbs, usually associated with uncomfortable sensations in the legs and sleep disorders. In general, two clinical forms of RLS are described: primary and secondary. Although primary RLS has a familial component, the underlying mechanism is still not fully understood but seems to be related to abnormalities in the dopaminergic and glutamatergic pathways of the central nervous system. The secondary forms of the syndrome are associated with iron deficiency, renal failure, pregnancy, diabetes mellitus, peripheral neuropathy, and several rheumatologic disorders such as rheumatoid arthritis and Sjögren's syndrome. In a few clinical trials, an increased frequency of RLS has been reported in patients with spondyloarthritis. In this report, a case of coexistence of spondyloarthritis and RLS is presented, showing satisfactory improvement with conservative treatment and additionally adding naproxen. Anemia of chronic disease occurring in rheumatic diseases, and associated iron deficiency may contribute to the development of RLS.

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.

Potential therapeutic benefit of spinal cord stimulation in restless legs syndrome: scoping review and mechanistic considerations.

BACKGROUND: Restless legs syndrome (RLS) is a prevalent sensorimotor disorder that can dramatically impair sleep quality, daytime function, and quality of life. Although many patients benefit from standard pharmacological therapy, some patients suffer from insufficient treatment response or medication intolerance. Novel treatment approaches are therefore necessary. OBJECTIVE: Given the overlap between RLS and pain syndromes in both pathophysiological mechanisms and certain treatment options, we aimed to perform a scoping review of the available evidence on spinal cord stimulation (SCS) for RLS and discuss potential mechanistic implications. METHODS: We identified a total of 16 cases of patients with RLS who underwent SCS, all from case reports or case series. DISCUSSION: The published evidence is insufficient to assess SCS efficacy in patients with RLS, but SCS remains a promising investigational therapy in RLS on the basis of its potential mitigatory effects in the central hyperexcitability of the sensorimotor cortex through neuromodulation of spinal, subcortical, and cortical areas. A call for further research in this field is presented, with suggestions for future directions and trial designs.

Incident mental health episodes after initiation of gabapentinoids vs. dopamine agonists for early-onset idiopathic restless legs syndrome.

Limited long-term safety information exists for gabapentinoid treatment of idiopathic restless legs syndrome (RLS). We estimated incident mental health-related emergency department visits and hospitalizations with a primary mental health diagnosis (primary outcome) among early-onset idiopathic RLS patients following first-line treatment initiation and examined outcome risk with gabapentinoids compared with dopamine agonists (DAs). A retrospective cohort study was conducted using administrative claims data from 2012 to 2019. Adults with early-onset (18-44 years) idiopathic RLS initiating either gabapentinoids or DAs within 60 days of new diagnosis were followed up to two years. Incidence rates were calculated and a log-binomial regression model with propensity score weighting estimated relative risk of the outcome and of substance use disorders (SUDs) as a secondary analysis with gabapentinoids. Among a cohort of 6,672 patients, 4,986 (74.7%) initiated DAs and 1,686 (25.3%) gabapentinoids. Incidence of the primary outcome (49.8 [95% CI 40.8-69.3] per 1,000 person-years) and SUDs (49.5 [95% CI 40.6-59.9] per 1,000 person-years) were higher in the gabapentinoid group compared with the DA group. A statistically significant risk of mental health diagnoses with gabapentinoids was not detected, but SUD risk was significant after covariate adjustment. High-risk mental health comorbidities (i.e., SUDs) should be considered when initiating RLS treatments.

Restless legs syndrome in multiple sclerosis patients: Prevalence, impact, and association with disease-modifying therapies in a Saudi Arabian pilot study.

BACKGROUND: Restless legs syndrome (RLS) emerges as a notable sleep disorder characterized by distressing sensations within the lower extremities. Its prevalence appears to be higher among patients afflicted with multiple sclerosis (MS) compared to the general population. Despite this observation, the understanding of the intricacies of RLS and its repercussions within the context of MS patients in Saudi Arabia remains limited. METHODS: Employing a cross-sectional design, a comprehensive investigation was undertaken at King Fahad Armed Forces Hospital in Jeddah, Saudi Arabia, spanning from November 2021 to March 2022. A cohort of 66 individuals diagnosed with MS was recruited and subjected to an assessment for RLS employing the revised diagnostic criteria outlined by the International Restless Legs Syndrome Study Group (IRLSSG). Furthermore, the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Sleepiness Scale were employed to gage the extent of RLS's impact on sleep quality and daily functioning. RESULTS: The prevalence of RLS amidst the MS cohort was determined to be 30.4%. An observable association was discerned between RLS presence and higher scores on the Expanded Disability Status Scale (p < 0.001), along with diminished sleep quality scores (p < 0.001) and elevated fatigue scores based on IRLSSG criteria (p < 0.001). Within the studied MS cases, 98.5 % exhibited the relapsing-remitting subtype. Further investigation demonstrated that patients treated with Fingolimod or Ocrevus presented normal IRLSSG scores, whereas those undergoing Rituximab treatment manifested an even distribution between normal and moderate scores. Correspondingly, patients receiving interferons showcased 72.2 % with normal scores and 27.8 % with mild scores. Notably, a statistically significant variance in IRLSSG scores was observed when contrasting Fingolimod and Aubagio treatments (P < 0.001). CONCLUSION: The presence of RLS as a comorbidity in MS patients within the Saudi Arabian context emerges as a significant finding, exerting a discernible detrimental influence on both disability status and sleep quality. This study underscores the need for further investigations aimed at unraveling the intricate pathophysiological underpinnings, identification of risk factors, and exploration of therapeutic modalities for RLS in this population. Furthermore, additional research endeavors are warranted to elucidate the diverse impact of various disease-modifying therapies on clinical outcomes.

Effectiveness of exercise and pramipexole in the treatment of restless leg syndrome: Implications on the dopaminergic system and PTPRD.

OBJECTIVE: Dopaminergic dysfunction, iron reduction and variations in the PTPRD gene (protein tyrosine phosphatase receptor type delta) may be associated with restless leg syndrome (RLS). Here, we evaluate the effect of pramipexole (PPX) and exercise on genes and proteins associated with RLS and on sleep patterns in spontaneously hypertensive rats (SHR). METHODS: Animals were distributed into 4 groups: 1) Control (CTRL); 2) Exercise (EX); 3) Exercise and pramipexole (EX + PPX); and 4) Pramipexole (PPX). PPX treatment was performed daily (0.125 mg/kg), while exercise was conducted over 5 sessions per week, both for 4 weeks. RESULTS: EX + PPX increased the protein levels of PTPRD, reduced the protein levels of the enzyme tyrosine hydroxylase (TH) and improved sleep parameters in both cycles; on the other hand, the use of PPX reduced mRNA and protein levels of PTPRD and TH but improved the sleep pattern in the light cycle. However, in the dark cycle, pramipexole caused the worsening of symptoms. CONCLUSIONS: We suggest that the improvement in sleep pattern by EX + PPX may be associated with the increased protein levels of PTPRD and that EX + PPX can reverse the negative effects of PPX.

Restless Legs Syndrome and Other Common Sleep-Related Movement Disorders.

OBJECTIVE: This article reviews common sleep-related movement disorders, including their clinical description, epidemiology, pathophysiology (if known), and evaluation and management strategies. This article will provide the reader with a good foundation for approaching concerns that are suggestive of sleep-related movement disorders to properly evaluate and manage these conditions. LATEST DEVELOPMENTS: α2δ Ligands, such as gabapentin enacarbil, can be used for the initial treatment of restless legs syndrome (RLS) or in those who cannot tolerate, or have developed augmentation to, dopamine agonists. Another option is the rotigotine patch, which has a 24-hour treatment window and may be beneficial for those who have developed augmentation with short-acting dopamine agonists. IV iron can improve RLS symptoms even in those whose serum ferritin level is between 75 ng/mL and 100 ng/mL. At serum ferritin levels greater than 75 ng/mL, oral iron will likely have minimal absorption or little effect on the improvement of RLS. Research has found an association between RLS and cardiovascular disease, particularly in people who have periodic limb movements of sleep. ESSENTIAL POINTS: RLS is the most common sleep-related movement disorder. Its pathophysiology is likely a combination of central iron deficiency, dopamine overproduction, and possibly cortical excitation. Treatment includes oral or IV iron. Dopaminergic medications can be very effective but often lead to augmentation, which limits their long-term use. Other sleep-related movement disorders to be aware of are sleep-related rhythmic movement disorder, nocturnal muscle cramps, sleep-related propriospinal myoclonus, sleep bruxism, and benign myoclonus of infancy.

Efficacy and safety of tonic motor activation (TOMAC) for medication-refractory restless legs syndrome: a randomized clinical trial.

STUDY OBJECTIVES: The purpose of this study was to evaluate the efficacy and safety/tolerability of bilateral high-frequency tonic motor activation (TOMAC) in patients with medication-refractory restless legs syndrome (RLS). METHODS: RESTFUL was a multicenter, randomized, double-blind, sham-controlled trial in adults with medication-refractory moderate-to-severe primary RLS. Participants were randomized 1:1 to active or sham TOMAC for a double-blind, 4-week stage 1 and all received active TOMAC during open-label, 4-week stage 2. The primary endpoint was the Clinical Global Impressions-Improvement (CGI-I) responder rate at the end of stage 1. Key secondary endpoints included change to International RLS Study Group (IRLS) total score from study entry to the end of stage 1. RESULTS: A total of 133 participants were enrolled. CGI-I responder rate at the end of stage 1 was significantly greater for the active versus sham group (45% vs. 16%; Difference = 28%; 95% CI 14% to 43%; p = .00011). At the end of stage 2, CGI-I responder rate further increased to 61% for the active group. IRLS change at the end of stage 1 improved for the active versus sham group (-7.2 vs. -3.8; difference = -3.4; 95% CI -1.4 to -5.4; p = .00093). There were no severe or serious device-related adverse events (AEs). The most common AEs were mild discomfort and mild administration site irritation which resolved rapidly and reduced in prevalence over time. CONCLUSIONS: TOMAC was safe, well tolerated, and reduced symptoms of RLS in medication-refractory patients. TOMAC is a promising new treatment for this population. CLINICAL TRIAL: Noninvasive Peripheral Nerve Stimulation for Medication-Refractory Primary RLS (The RESTFUL Study); clinicaltrials.gov/ct2/show/NCT04874155; Registered at ClinicalTrials.gov with the identifier number NCT04874155.

Choroidal parameters and Restless Legs Syndrome.

To obtain reliable data, standardized measurements are needed, therefore the aim of this letter is to clarify some points.

Long-term efficacy and safety of tonic motor activation for treatment of medication-refractory restless legs syndrome: A 24-Week Open-Label Extension Study.

STUDY OBJECTIVES: To evaluate long-term efficacy and safety of tonic motor activation (TOMAC) for treatment of medication-refractory moderate-to-severe primary restless legs syndrome (RLS). METHODS: In the parent study (RESTFUL), adults with refractory RLS were randomized to active TOMAC or sham for 4 weeks followed by 4 weeks of open-label active TOMAC. In the extension study, earlier RESTFUL completers comprised the control group (n = 59), which was followed for 24 weeks with no TOMAC intervention, and later RESTFUL completers compromised the treatment group (n = 44), which received 24 additional weeks of open-label active TOMAC followed by no intervention for 8 weeks. The primary endpoint was Clinician Global Impressions-Improvement (CGI-I) responder rate at week 24 compared to RESTFUL entry. RESULTS: CGI-I responder rate improved from 63.6% (95% CI, 49.4 to 77.9%) at RESTFUL completion to 72.7% (95% CI, 58.2 to 83.7%) at week 24 for the treatment group versus 13.6% (95% CI, 7.0 to 24.5%) at week 24 for the control group (p < 0.0001). Mean change in International RLS Rating Scale (IRLS) score improved from -7.4 (95% CI, -5.6 to -9.2) at RESTFUL completion to -11.3 points (95% CI, -8.8 to -13.9) at week 24 for the treatment group versus -5.4 (95% CI, -3.7 to -7.2) at week 24 for control group (p = 0.0001). All efficacy endpoints partially reverted during cessation of treatment. There were no grade 2 or higher device-related adverse events. CONCLUSIONS: TOMAC remained safe and efficacious for >24 total weeks of treatment with partial reversion of benefits upon cessation. CLINICAL TRIAL: Extension Study Evaluating NTX100 Neuromodulation System for Medication-Refractory Primary RLS; clinicaltrials.gov/ct2/show/NCT05196828; Registered at ClinicalTrials.gov with the identifier number NCT05196828.

Ferric carboxymaltose effects on restless legs syndrome and on brain iron in patients with iron deficiency anemia.

OBJECTIVE: Brain iron status is fundamental in RLS pathogenesis. The aim of this study was to determine the clinical efficacy and brain iron concentration improvement in RLS patients with IDA, using 1500 mg FCM. METHODS: This is a randomized, double-blinded, placebo-controlled study. RLS patients with IDA were grouped into either 1500 mg FCM or placebo. The primary outcomes were the change from baseline on the International Restless Legs Syndrome Study Group scale (IRLS) and brain iron measured by QSM and R2∗. RESULTS: A total of 18 RLS patients with IDA were enrolled, 10 in the FCM group and 8 in the placebo. At the week 6 endpoint, the FCM group showed significant improvement in both IRLS (-13.60 ± 9.47 vs. -3.63 ± 5.40, p = 0.011) and VAS (-40.50 ± 28.81 vs. -0.63 ± 28.28, p = 0.004) from baseline. Change from baseline with R2∗ techniques showed a treatment effect for the thalamus and QSM technique for both the substantia nigra and pulvinar. A correlation was proved between the IRLS difference and the difference of QSM in thalamus (p = 0.028). CONCLUSION: This study demonstrates that 1500 mg FCM effectively treats RLS symptoms in IDA patients over six weeks, with MRI measurements of improved brain iron content serving as a potential biomarker for RLS patients.