Restless Legs Syndrome Augmentation Research Articles

1224 Management of Dopaminergic Augmentation of Restless Legs Syndrome with Concurrent High Dose Benzodiazepine Therapy

1224 Management of Dopaminergic Augmentation of Restless Legs Syndrome with Concurrent High Dose Benzodiazepine Therapy

Exploring the causes of augmentation in restless legs syndrome.

Long-term drug treatment for Restless Legs Syndrome (RLS) patients can frequently result in augmentation, which is the deterioration of symptoms with an increased drug dose. The cause of augmentation, especially derived from dopamine therapy, remains elusive. Here, we review recent research and clinical progress on the possible mechanism underlying RLS augmentation. Dysfunction of the dopamine system highly possibly plays a role in the development of RLS augmentation, as dopamine agonists improve desensitization of dopamine receptors, disturb receptor interactions within or outside the dopamine receptor family, and interfere with the natural regulation of dopamine synthesis and release in the neural system. Iron deficiency is also indicated to contribute to RLS augmentation, as low iron levels can affect the function of the dopamine system. Furthermore, genetic risk factors, such as variations in the BTBD9 and MEIS1 genes, have been linked to an increased risk of RLS initiation and augmentation. Additionally, circadian rhythm, which controls the sleep-wake cycle, may also contribute to the worsening of RLS symptoms and the development of augmentation. Recently, Vitamin D deficiency has been suggested to be involved in RLS augmentation. Based on these findings, we propose that the progressive reduction of selective receptors, influenced by various pathological factors, reverses the overcompensation of the dopamine intensity promoted by short-term, low-dose dopaminergic therapy in the development of augmentation. More research is needed to uncover a deeper understanding of the mechanisms underlying the RLS symptom and to develop effective RLS augmentation treatments.

Vitamin D and Restless Legs Syndrome: A Review of Current Literature.

This review presents a detailed summary of the current literature regarding RLS and vitamin D deficiency. To our knowledge it is the first review of its kind. We review the prevalence of vitamin D deficiency in RLS as well as the evidence for the use of vitamin D supplementation in RLS management. We further examine the literature for proteomic and genetic evidence of a role for vitamin D in the pathogenesis of RLS. An alteration in vitamin D binding protein in RLS is one of the most consistent findings in the proteomic studies. Furthermore, we examine the interaction of vitamin D with calcium, phosphorus, and parathyroid hormone and the possible role of these connections in RLS. We also explore the possible nexus between RLS and vitamin D in renal disease, cardiovascular and cerebrovascular disease as well as inflammation. In addition, we review the potential interaction between vitamin D and RLS with iron, dopamine and other neurotransmitter systems including the endogenous opiate, serotoninergic, glutamatergic and adenosinergic systems. We also explore the role of vitamin D in RLS Augmentation (i.e., the paradoxical worsening of RLS symptoms when dopaminergic agents are used as a therapy for RLS). Although the literature is not entirely consistent in affirming vitamin D deficiency in RLS or the amelioration of RLS symptoms with vitamin D therapy, the collective studies overall indicate that vitamin D deficiency is common enough in RLS patients to suggest that RLS patients should have their vitamin D levels checked and any deficiency corrected as a standard of care. Highlights Patients with Restless Legs Syndrome (RLS) may be deficient in vitamin D and therapy with vitamin D may ameliorate RLS. We present the first review dedicated solely to evaluating the relationship between RLS and vitamin D and present a case for the role of vitamin D in RLS pathogenesis.

Factors associated with augmentation in patients with restless legs syndrome

Background and purposeAugmentation is a paradoxical reaction mainly to dopaminergic medication in patients with restless legs syndrome (RLS), but the exact pathomechanism remains unclear. The aim of this study was to identify factors associated with augmentation in RLS patients.MethodsRLS patients with and without current or previous augmentation were recruited. Demographic characteristics, history of smoking, questionnaires for depression, alexithymia, and impulsivity, and RLS severity were obtained.ResultsWe included 122 patients, of whom half had a history of augmentation. Patients with augmentation had a longer disease duration (p = 0.001), had higher RLS severity scores (p = 0.013), had higher levodopa equivalent doses (p < 0.001), had higher scores for alexithymia (p = 0.028), had higher prevalence of impulse control disorders (p < 0.001), more often had a history of smoking (p = 0.039), were more often currently smoking (p = 0.015), and had more average pack‐years (p = 0.016).ConclusionsHere, we describe several factors commonly associated with augmentation in RLS. These may help clinicians to screen and treat patients carefully to avoid the challenging side effect of augmentation.

Birds of a Feather Flock Together: Disadvantageous Decision Making in Augmented Restless Legs Syndrome Patients with and without Impulse Control Disorders.

Background: Augmentation (AUG) in patients with restless legs syndrome (RLS) can be associated with impulse control disorder (ICD) symptoms, such as compulsive sexual behavior, gambling disorder or compulsive shopping. In this study, we wanted to assess whether RLS patients with AUG differ in decision making from those patients who have augmentation and in addition ICD symptoms (AUG + ICD) in a post hoc analysis of a patient cohort assessed in a previous study. Methods: In total, 40 RLS patients with augmentation (19 AUG + ICD, 21 AUG without ICDs) were included. RLS diagnosis, severity, and diagnosis of augmentation were made by sleep disorder specialists. ICD symptoms were assessed using semi-structured interviews. All patients performed the beads task, which is an information sampling task where participants must decide from which of the two cups colored beads were drawn. Results were compared to 21 healthy controls (HC). Results: There was no difference in information sampling or irrational decision making between AUG and AUG + ICD patients (p = 0.67 and p = 1.00, respectively). Both patient groups drew less beads and made more irrational decisions than HC (all p-values < 0.03, respectively). Conclusions: Our results suggest that augmentation itself is associated with poorer decision making even in the absence of ICD symptoms. Further studies are necessary to explore whether rapid and hasty decision making are a harbinger of augmentation in RLS.

Augmentation in restless legs syndrome: an eye tracking study on emotion processing.

ObjectiveTo assess emotional processing and alexithymia in patients with restless legs syndrome (RLS) with augmentation versus those who never had augmentation.MethodsWe recruited 26 patients who had a history of augmentation (AUG), either current or past, 27 RLS patients treated with dopamine agonists who never had augmentation (RLS controls), and 21 healthy controls (HC). All participants were screened for impulse control disorders (ICDs). Alexithymia was assessed by means of the Toronto Alexithymia Scale – 20 (TAS‐20). Facial emotion recognition was tested through an eye‐tracking task. Furthermore, all participants performed neuropsychological tests assessing global cognitive status, impulsivity, anxiety, and depression.ResultsICD symptoms occurred more frequently in AUG patients than in RLS controls (P = 0.047). Patients with AUG scored higher on the TAS‐20 (P = 0.007) and the attentional subdomain of an impulsivity scale (BIS‐11; P = 0.015) compared to HC. Patients with AUG also performed worse on the facial emotion recognition task relative to RLS controls (P = 0.009) and HC (P = 0.003). We found a group difference for the time to first fixation and the fixation count in the mouth region (P = 0.019 and P = 0.021, respectively). There were no other differences in the eye tracking examination.InterpretationThis study showed evidence of poorer emotional processing in patients who had augmentation compared to RLS patients without augmentation and healthy controls. The altered exploration pattern of faces and the higher alexithymia scores suggest abnormalities in emotion processing in patients with augmentation.

Drug Treatment of Restless Legs Syndrome in Older Adults.

Restless legs syndrome (RLS) has a high prevalence in the elderly and can impact sleep quality and sleep quantity, reduce quality of life (QoL), and increase the risk of falls during episodes of night-time ambulation. In patients unable to verbalize their sensory symptoms, certain behavioral cues may help with the diagnosis. A state of brain iron deficiency could play a central role in the pathophysiology of RLS and be upstream to a series of dysfunctions that are not limited to the dopaminergic system. Management should initially emphasize lifestyle modifications and reduction of all possible iatrogenic contributors while maintaining a state of normal-high peripheral iron stores. Oral iron, in patients with ferritin levels < 75μg/dL, appears to be effective, although iron infusions should be considered when more immediate benefit or oral iron have not been effective. When other attempts fail and patients continue to experience chronic RLS symptoms substantially interfering with QoL, pharmacological agents may present a favorable benefit versus risk profile. Such agents may include α-2-δ drugs or dopaminergic agents, after careful consideration of the risk of RLS augmentation with the latter class. In patients with established RLS augmentation from the use of dopaminergic drugs, the addition of α-2-δ agents or low-dose opioids, with subsequent slow tapering of dopaminergic agents, is recommended. With any of these agents, caution should be made with regard to the risk of drug-drug interactions and altered pharmacokinetics in this fragile population. Although showing excellent long-term safety data in non-elderly adults with RLS, studies are needed to ascertain that such treatments are effective and well tolerated in older adults.

Treatment of restless legs syndrome: Evidence-based review and implications for clinical practice (Revised 2017)§.

The objective of the current review was to update the previous evidence-based medicine review of treatments for restless legs syndrome published in 2008. All randomized, controlled trials (level I) with a high quality score published between January 2007 and January 2017 were reviewed. Forty new studies qualified for efficacy review. Pregabalin, gabapentin enacarbil, and oxycodone/naloxone, which did not appear in the previous review, have accrued data to be considered efficacious. Likewise, new data enable the modification of the level of efficacy for rotigotine from likely efficacious to efficacious. Intravenous ferric carboxymaltose and pneumatic compression devices are considered likely efficacious in idiopathic restless legs syndrome. Bupropion and clonidine were reviewed, but the lack of data determined a rating of insufficient evidence for efficacy. The following interventions continue to be considered efficacious as in 2008: levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin. Bromocriptine, oxycodone, carbamazepine, and valproic acid are considered likely efficacious. Oral iron is nonefficacious in iron-sufficient subjects, but its benefit for patients with low peripheral iron status has not been adequately evaluated. Restless legs syndrome augmentation has been identified as a significant long-term treatment complication for pramipexole more than pregabalin and possibly for all dopaminergic agents more than α2δ ligands. Therefore, special monitoring for augmentation is required for all dopaminergic medications as well as tramadol. Other drugs also require special safety monitoring: cabergoline, pergolide, oxycodone, methadone, tramadol, carbamazepine, and valproic acid. Finally, we also highlighted gaps and needs for future clinical research and studies of restless legs syndrome. © 2018 International Parkinson and Movement Disorder Society.

Restless legs syndrome augmentation among Japanese patients receiving pramipexole therapy: Rate and risk factors in a retrospective study.

To investigate the rate of and risk factors for restless legs syndrome (RLS) augmentation in Japanese patients receiving pramipexole (PPX) treatment. Records of 231 consecutive patients with idiopathic RLS who received PPX therapy for more than one month in a single sleep disorder center were analyzed retrospectively. Augmentation was diagnosed based on the Max Planck Institute criteria; associated factors were identified by logistic regression analysis. Mean age at PPX initiation was 60.6 ± 14.9 years and mean treatment duration was 48.5 ± 26.4 months. Augmentation was diagnosed in 21 patients (9.1%). Daily PPX dose and treatment duration were significantly associated with augmentation. By analyzing the receiver operating characteristic curve, a PPX dose of 0.375 mg/day was found to be the optimal cut-off value for predicting augmentation. After stratifying patients according to PPX treatment duration, at median treatment duration of 46 months, optimal cut-off values for daily doses were 0.375 and 0.500 mg/day for <46 months and ≥46 months of treatment, respectively. The RLS augmentation with PPX treatment in Japanese patients was occurred at rate of 9.1%, being quite compatible with previously reported rates in Caucasian patients. The symptom could appear within a relatively short period after starting the treatment in possibly vulnerable cases even with a smaller drug dose. Our results support the importance of keeping doses of PPX low throughout the RLS treatment course to prevent augmentation.

Augmentation and impulsive behaviors in restless legs syndrome: Coexistence or association?

Editors' Note: In WriteClick this week, Dr. Nirenberg responds to “Augmentation and impulsive behaviors in restless legs syndrome: Coexistence or association?” with the hypothesis that augmentation in restless legs syndrome may be a forme fruste of dopamine agonist withdrawal syndrome. Authors Djamshidian et al. report no association between augmentation and medication nonadherence, but agree with monitoring these patients closely for addictive behaviors. In reference to “Spatial-temporal functional mapping of language at the bedside with electrocorticography,” Drs. Babajani-Feremi et al. and authors Wang et al. discuss the use of high-gamma …

Spatial-temporal functional mapping of language at the bedside with electrocorticography.

Editors' Note: In WriteClick this week, Dr. Nirenberg responds to “Augmentation and impulsive behaviors in restless legs syndrome: Coexistence or association?” with the hypothesis that augmentation in restless legs syndrome may be a forme fruste of dopamine agonist withdrawal syndrome. Authors Djamshidian et al. report no association between augmentation and medication nonadherence, but agree with monitoring these patients closely for addictive behaviors. In reference to “Spatial-temporal functional mapping of language at the bedside with electrocorticography,” Drs. Babajani-Feremi et al. and authors Wang et al. discuss the use of high-gamma electrocorticography, electrocortical stimulation mapping, …

‘Cycling’ with long‐acting dopamine agonists for augmentation in restless legs syndrome

‘Cycling’ with long‐acting dopamine agonists for augmentation in restless legs syndrome

Management of augmentation of restless legs syndrome with rotigotine: a 1-year observational study

AimThe aim of this study is to assess the effect of switching to rotigotine transdermal patch on severity of restless legs syndrome (RLS) in patients who experienced acute augmentation with previous oral dopaminergics. MethodsIn this 13-month observational study, adults with moderate-to-severe RLS and augmentation were switched to rotigotine per the physician’s independent decision. Assessments included Clinical Global Impression severity score (CGI-1); (primary), treatment regimen for switching (secondary), RLS-6, International RLS Study Group Rating Scale (IRLS), and augmentation severity rating scale (ASRS). ResultsA total of 99 patients received rotigotine, of whom 46 completed observational period, and 43 were assessed for effectiveness. A total of 5 patients switched to rotigotine after a >1-day drug holiday, 23 switched overnight, 9 had an overlapping switch, and 6 received ongoing oral dopaminergics with rotigotine for ≥28 days. Of the 99 patients, 57 took concomitant RLS medications (excluding switching medications) on at least 1 day. At the final visit, median change in CGI-1 (Hodges–Lehman estimate [95% CI]) was −2.0 (–2.5, −1.50); 37 of the 43 patients improved by ≥1 CGI-1 category, and 16 of 43 were responders (≥50% improvement). RLS-6 and IRLS scores also improved. Patients had median ASRS of 0 at the final visit indicating “no worsening/occurrence of augmentation.” ASRS item 1 showed a shift in mean time of symptom onset (24-h clock) from 12:38 (baseline) to 18:25 (final visit). Most common reasons for withdrawal of rotigotine were adverse events (26 patients) and lack of efficacy (14 patients). ConclusionsSwitching from oral therapies to rotigotine was effective in improving RLS symptoms in 37 of the 43 patients (from the original population of 99 patients) who remained in the study over 13 months. Clinical trial registrationClinicalTrials.govNCT01386944.

Augmentation in Restless Legs Syndrome: Treatment with Gradual Medication Modification.

Dopaminergic drugs can cause augmentation during the treatment of restless legs syndrome (RLS). We previously reported that sudden withdrawal of dopaminergic treatment was poorly tolerated. We now report our experience with gradual withdrawal of the dopaminergic drug during the drug substitution process using a retrospective chart review with comparison to previous data. Seven patients with RLS and dopaminergic drug-induced augmentation were treated with a gradual withdrawal of the offending drug and replacement with an alternative medication. Compared to sudden withdrawal, measured outcomes were similar but gradual tapering was better tolerated. We conclude that for augmentation in RLS, gradual tapering of the augmentation-inducing dopaminergic drug is better tolerated than sudden withdrawal. The optimal approach to treating augmentation has not been established and may differ between patients. Further study with direct comparison of strategies and a larger patient population is needed to confirm our preliminary observations.

First 1-year Real-life Study to Assess Management of Augmentation of Restless Legs Syndrome by Switching to Rotigotine Transdermal System (P7.304)

First 1-year Real-life Study to Assess Management of Augmentation of Restless Legs Syndrome by Switching to Rotigotine Transdermal System (P7.304)

Augmentation in restless legs syndrome patients in Korea.

Augmentation has been known as the major complication of long-term dopaminergic treatment of restless legs syndrome (RLS). However, there have been no reports on the prevalence of augmentation in Korea. Thus, we aimed to assess the rate of augmentation and evaluate related factors in Korean RLS patients. Ninety-four idiopathic RLS patients who have been treated over a period of at least 6 months were enrolled. Thirty subjects were treated with a dopamine agonist only, and 64 were treated with a dopamine agonist and alpha two delta ligands. We assessed the clinical characteristics of those RLS subjects and evaluated the rate of augmentation. Augmentation was assessed using the NIH criteria for augmentation by two RLS experts independently. Eleven subjects (11.7%) were classified as having definitive or highly suggestive clinical indication of augmentation. In comparing the augmentation group with the non-augmentation group, there were no significant differences of baseline clinical characteristics. Four (13.3%) of the dopamine agonists monotherapy group and seven (10.9%) of the combination therapy group were categorized as augmentation. There was no significant difference in the augmentation rate between these two groups. We found an 11.7% augmentation rate in Korean RLS subjects. There was no difference in the rate of RLS augmentation between the dopaminergic monotherapy group and the combined treatment group. It may be related with using a similar dosage of dopaminergic drugs.

Is there a polysomnographic signature of augmentation in restless legs syndrome?

ObjectiveAugmentation of restless legs syndrome (RLS) is a potentially severe side-effect of dopaminergic treatment. Data on objective motor characteristics in augmentation are scarce. The aim of this study was to investigate in detail different variables of leg movements (LM) in untreated, treated, and augmented RLS patients. MethodsForty-five patients with idiopathic RLS [15 untreated, 15 treated (non-augmented), 15 augmented] underwent RLS severity assessment, one night of video-polysomnography with extended electromyographic montage, and a suggested immobilization test (SIT). ResultsStandard LM parameters as well as periodicity index (PI) and muscle recruitment pattern did not differ between the three groups. The ultradian distribution of periodic leg movements (PLM) in sleep during the night revealed significant differences only during the second hour of sleep (P < 0.05). However, augmented patients scored highest on RLS severity scales (P < 0.05) and were the only group with a substantial number of PLM during the SIT. ConclusionThis study demonstrates that polysomnography is of limited usefulness for the diagnosis and evaluation of RLS augmentation. In contrast, the SIT showed borderline differences in PLM, and differences on subjective scales were marked. According to these results, augmentation of RLS is a phenomenon that predominantly manifests in wakefulness.

Comparison of Pregabalin with Pramipexole for Restless Legs Syndrome

BackgroundDopaminergic medications relieve symptoms of the restless legs syndrome (RLS) but have the potential to cause iatrogenic worsening (augmentation) of RLS with long-term treatment. Pregabalin may be an effective alternative.MethodsIn this 52-week, randomized, double-blind trial, we assessed efficacy and augmentation in patients with RLS who were treated with pregabalin as compared with placebo and pramipexole. Patients were randomly assigned to receive 52 weeks of treatment with pregabalin at a dose of 300 mg per day or pramipexole at a dose of 0.25 mg or 0.5 mg per day or 12 weeks of placebo followed by 40 weeks of randomly assigned active treatment. The primary analyses involved a comparison of pregabalin and placebo over a period of 12 weeks with use of the International RLS (IRLS) Study Group Rating Scale (on which the score ranges from 0 to 40, with a higher score indicating more severe symptoms), the Clinical Global Impression of Improvement scale (which was used to assess the proportion of patients with symptoms that were “very much improved” or “much improved”), and a comparison of rates of augmentation with pregabalin and pramipexole over a period of 40 or 52 weeks of treatment.ResultsA total of 719 participants received daily treatment, 182 with 300 mg of pregabalin, 178 with 0.25 mg of pramipexole, 180 with 0.5 mg of pramipexole, and 179 with placebo. Over a period of 12 weeks, the improvement (reduction) in mean scores on the IRLS scale was greater, by 4.5 points, among participants receiving pregabalin than among those receiving placebo (P<0.001), and the proportion of patients with symptoms that were very much improved or much improved was also greater with pregabalin than with placebo (71.4% vs. 46.8%, P<0.001). The rate of augmentation over a period of 40 or 52 weeks was significantly lower with pregabalin than with pramipexole at a dose of 0.5 mg (2.1% vs. 7.7%, P=0.001) but not at a dose of 0.25 mg (2.1% vs. 5.3%, P=0.08). There were six cases of suicidal ideation in the group receiving pregabalin, three in the group receiving 0.25 mg of pramipexole, and two in the group receiving 0.5 mg of pramipexole.ConclusionsPregabalin provided significantly improved treatment outcomes as compared with placebo, and augmentation rates were significantly lower with pregabalin than with 0.5 mg of pramipexole. (Funded by Pfizer; ClinicalTrials.gov number, NCT00806026.)

Management of augmentation in restless legs syndrome with pramipexole extended-release

Introduction Dopamine agonists represent the first- line treatment in restless legs syndrome (RLS), however in the long term, a substantial portion of patients will develop augmentation, which is a severe drug-related exacerbation of symptoms and the main reason of late therapy withdrawal. The mechanism underlining augmentation is unknown and no guidelines are available to treat it. Objective of the study was to evaluate the role of extended release dopaminoagonist in the management of augmentation. Materials and methods Twenty-four consecutive RLS outpatients (10M,14F, mean age 68.4 ± 10yrs) treated with immediate- release dopamine agonists (pramipexole 11 pts, ropinirole 7 pts, cabergoline 1 pts, levodopa 1 pts, combined DA treatment 4 pts) for a mean period of 6.7yrs ± 5 were diagnosed as affected by severe, clinically relevant augmentation Since an inverse relationship between DA half-life and augmentation has been postulated we decided to switch the treatment to the long-acting extended release (ER) formula of pramipexole, given at 5pm and progressively increased until a satisfactory control of the symptoms was achieved (at a mean dose of 0.75mg, range 0.375–1.125mg), accompanied by a complete withdrawal of the otherdopaminergic agents. Results Resolution of augmentation was observed in all patients in 2–3weeks and persisted so far for a mean follow- up interval of 7months. Mean dose of dopamine agonist was not significanty different before and after the shift of therapy (pramipexole equivalent dosage during augmentation 0.84mg ± 0.51 vs. extended release pramipexole 0.67mg ± 0.28). RLS severity scale decreased from 32 ± 4 to 16 ± 9 ( p Conclusion Pramipexole extended release might represent an easy, safe and fast pharmacological option that needs to be evaluated with prospective and controlled investigations. The findings support the hypothesis that the duration of action of the drug plays a key role in the mechanism of augmentation.

Augmentation in restless legs syndrome: poor response to sudden withdrawal of dopaminergic therapy

Augmentation in restless legs syndrome: poor response to sudden withdrawal of dopaminergic therapy Roger Kurlan, Marcie Rabin Atlantic Neuroscience Institute, Overlook Medical Center, Summit, NJ, USA Background: Augmentation is a common complication of long-term dopaminergic therapy for restless legs syndrome (RLS). Methods: We conducted a retrospective chart review of patients with RLS and augmentation to learn more about the condition, including response to therapy. Results: We identified 14 patients (nine women, five men; mean age 65.7 years; mean duration of RLS 23.6 years) with augmentation. Thirteen patients were taking a dopamine agonist and one was taking levodopa. Mean duration of dopaminergic therapy was 5.5 years. The dopaminergic drug was withdrawn at one time and replaced by gabapentin (n = 9), tramadol (n = 5), clonazepam (n = 4), propoxyphene (n = 2), or codeine (n = 1). Seven patients required more than one drug to control symptoms. The mean time until augmentation resolved was 12.5 (range 1&ndash;43) weeks, shortest when gabapentin was used first (2.6 weeks) and longer when clonazepam (14.9 weeks) or tramadol (22.3 weeks) was the initial replacement drug. Conclusion: Augmentation was the most common problem associated with referral of a patient with RLS to a movement disorders specialist, yet referring physicians did not appear to know how to treat it. Regaining satisfactory control of symptoms following sudden withdrawal of the offending dopaminergic drug was difficult, taking longer than 3 months on average. The optimum treatment of drug-induced augmentation is unclear and needs further investigation. Keywords: restless legs syndrome, dopamine agonists, levodopa, augmentation