Accepted Manuscript Title: Restless legs syndrome: Clinical presentation, diagnosis and treatment Author: Subhashie Wijemanne, Joseph Jankovic PII: DOI: Reference:
S1389-9457(15)00647-4 http://dx.doi.org/doi:10.1016/j.sleep.2015.03.002 SLEEP 2708
To appear in:
Sleep Medicine
Received date: Revised date: Accepted date:
27-3-2014 28-2-2015 2-3-2015
Please cite this article as: Subhashie Wijemanne, Joseph Jankovic, Restless legs syndrome: Clinical presentation, diagnosis and treatment, Sleep Medicine (2015), http://dx.doi.org/doi:10.1016/j.sleep.2015.03.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Restless Legs Syndrome: Clinical Presentation, Diagnosis and Treatment Subhashie Wijemanne, MD, MRCP, Joseph Jankovic, MD Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas, USA
Address correspondence to:
Joseph Jankovic, MD Professor of Neurology, Distinguished Chair in Movement Disorders, Director of Parkinson’s Disease Center and Movement Disorders Clinic Department of Neurology Baylor College of Medicine 6550 Fannin, Suite 1801 Houston, Texas 77030 Tel: 713-798-5998 Fax: 713-798-6808 Email: [email protected] Web: www.jankovic.org
Highlights
Restless legs syndrome (RLS) is a circadian disorder of sensory-motor integration Augmentation is a major therapy related complication of dopaminergic medications α2δ ligands such as gabapentin are favored over dopamine agonist as first-line agents
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Opioids can be used as monotherapy or in combination in refractory RLS
Abstract Restless legs syndrome (RLS) is a circadian disorder of sensory-motor integration which may be related to genetically-determined dysregulation of iron transport across the blood brain barrier. Dopamine agonists (DA) have been considered the first line therapy but with the growing appreciation of problems associated with long-term treatment, particularly augmentation and impulse control disorder, alpha-2-delta drugs, such as gabapentin, are now considered the first line of treatment in patients with troublesome RLS. Opioids can be considered as alternative therapy, particularly in patients with DA-related augmentation. In more severe cases, combination therapy may be required. Intravenous iron therapy may be considered on those patients with refractory RLS.
Keywords Restless legs syndrome, augmentation, dopamine agonist, pramipexole, ropinirole, rotigotine, methadone, gabapentin
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Introduction Restless legs syndrome (RLS), also referred to as Willis-Ekbom disease (WED), is a chronic neurological disorder that may require lifelong treatment [1]. Majority of patients with RLS respond well to currently available medications. One of the most challenging aspects of treating RLS is the occurrence of medication related complication namely augmentation (discussed in more detail below) and its management. A subset of patients’ may also progress to severe or refractory RLS (“malignant RLS”) which can be very disabling. This article summarizes different clinical presentations, diagnosis of RLS with an emphasis on management of RLS.
RLS is a circadian disorder of sensory-motor integration manifested by an urge or a need to move the limbs to stop unpleasant sensations in the evening or while at rest [1-4]. First described by Thomas Willis in 1685, it was Ekbom in 1945, who described essentially all the cardinal clinical features of the syndrome and coined the name “restless legs syndrome” [5]. In recognition of the contributions by these two pioneers, the nonprofit Restless Legs Syndrome Foundation was recently renamed as the Willis-Ekbom Disease Foundation [6].
The diagnosis of RLS is based on the 2012 revised International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria [7, 8]. Compared to the 2003 criteria, the 2012 version
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includes a 5th criteria to rule out RLS mimickers [9] and in addition, all the essential diagnostic criteria have to be met: 1) The urge to move the legs, usually but not always accompanied by or felt to be caused by uncomfortable and unpleasant sensations in the legs; 2) The urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting; 3) The urge to move the legs and any accompanying unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues; 4) The urge to move and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night than during the day; 5) The above features are not solely accounted for by other medical or behavioral conditions, such as myalgias, venous stasis, leg edema, arthritis, leg cramps [10], positional discomfort, habitual foot tapping, and other nocturnal sensory-motor symptoms.
Clinical Manifestations Descriptions of the uncomfortable sensation (in descending order of frequency) include: "need to move", "crawling", "tingling", "restless", “cramping”, “creeping", "pulling", "painful", "electric", "tension", "itching", “burning”, “prickly”, but unique, culturally-determined, terms such as “heebie jeebies", “wriggling magots”, “elvis legs”, “the shpilke”, and others [11, 12]. Typical RLS sensations are felt deep inside the muscles and bones of the legs but some patients describe sensations that are felt superficially in the skin [11]. In one study, 28 of 44 (64%) of patients had predominantly bilateral leg symptoms and 15 of 44 (34%) had predominantly unilateral symptoms; upper calf was the most frequently affected region (73%) [13]. As RLS progresses the symptoms may no longer be confined to the legs and may progress to the arms [13]. Akathisia is an abnormal state of excessive restlessness with an urge or the need to move but,
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unlike RLS, it is much more generalized and it does not have diurnal variation [3, 14]. The newly described, although very common, “leg stereotypy disorder”, is manifested by stereotypic, 1-2 Hz rhythmical, flexion-extension and abduction-adduction movements of the hips and flexionextension movements of the ankles while the individual is sitting with the toes of the foot pressed against the floor or when the legs are crossed [3]. In situations where the diagnosis is uncertain, the levodopa test (50% improvement in symptoms after 25/100 mg of carbidopa/levodopa) might be useful [15], but it should be noted that in clinical trials 15 - 40% did not respond to dopaminergic drugs. In addition to primary RLS, secondary causes of RLS include iron deficiency, pregnancy and end-stage renal disease. Neuropathy may be associated with RLS-like symptoms but usually without diurnal variation and typically accompanied by other neurological symptoms and deficits including sensory, motor and reflex abnormalities. Periodic limb movements of sleep (PLMS), present in over 80%-90% of RLS patients [16], consists of highly stereotyped movements that typically involve extension of the big toe with partial flexion of the ankle, knee, and sometimes the hip (“triple flexion”) and occasionally in the upper extremities [17]. Movements are usually bilateral but are not necessarily symmetrical or synchronous; they may predominate in one leg or alternate between legs. PLMS can occur in the upper extremities and is often manifested as repetitive flexion at the elbow. The duration of movement is typically between 1.5-2.5 seconds with a periodicity of between 20 and 40 seconds, although wide ranges of frequencies have been reported. Periodic limb movements can occur during wakefulness and are referred to as “periodic limb movements while awake” (PLMW) [18]. These are typically jerk-like movements with an appearance and distribution similar to PLMS, but with greater intensity and speed [18]. Periodic limb movements of sleep index
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(PLMSI), number of leg movements per hour, is one of the measures recorded by polysomnography (PSG). Specific criteria for recording and scoring periodic leg movements can be found in World Association of Sleep Medicine criteria [19]. Quantification of PLMS is currently used as an objective measure of assessing RLS [20]. However, the presence of PLMS is not essential to make a diagnosis of RLS and, therefore, an overnight PSG is not necessary for the diagnosis of RLS. The impact of RLS on sleep, particularly sleep-onset insomnia [21], contributes to the overall adverse impact on quality of life, often leading to serious psychosocial impairment [22, 23]. Disturbed sleep is usually the primary reason a patient seeks medical attention. Additionally, there is also a strong association between untreated RLS and depression [24]. With increasing disease severity and prominent sleep disruption, the circadian pattern can be overridden and symptoms may be present 24 hours a day [25]. Although it is well recognized that patients with RLS associated with renal disease have a higher mortality [26], there is some controversy whether patients with idiopathic RLS [27] also have a higher overall mortality [23]. One study reported an adjusted mortality hazard ratio of 1.92 (95% CI 1.03-3.56; p = 0.04, attributed to a variety of medical problems, but further studies are needed to confirm this observation [28].
Epidemiology Based on well conducted epidemiological studies the overall prevalence of RLS has been reported to range from 7% for any RLS to 2.7% for clinically apparent RLS [29]. For primary RLS (excluding secondary causes) the overall prevalence in the USA was estimated to be 2.4% and 1.5% for primary and clinically significant RLS [23]. RLS seems to be an age-related
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disorders, although symptoms can begin in childhood, and 38% of adults have reported the onset of symptoms before the ages of 20 years and 10% before the age of 10 years [16]. The overall prevalence of gender-adjusted primary RLS in the United States was estimated to be 2.4%, increasing with age from 1.4% (for ages 20–29) to 3.3% (for ages 60–69) and then decreasing to 1.7% for the oldest age group [23]. Studies from non-European countries show a relatively lower prevalence: 0.1% in Singapore [30], 0.9% in South Korea [31]. Females are affected twice as frequently as males across all population groups and ages [32]. However, RLS continues to remain grossly under-diagnosed [29, 33]. The relationship between RLS and Parkinson’s disease (PD) is controversial. Some studies have shown that up to 20% of patients with PD have RLS [34-37] but the preponderance of data suggests that RLS is not a risk factor for the eventual development of PD [38].
Genetics The presence of family history in RLS is common and when present, supports the diagnosis of RLS.Primary RLS is characterized by high familial aggregation suggesting a genetic component. Approximately 63% of patients report having at least one first-degree relative with the condition [16]. Despite intensive efforts, a monogenic cause for RLS has not been detected to date [39, 40]. Independent genome-wide association studies in diverse populations of Northern European origin have found six different genes that may play a role in RLS: BTBD9, MEIS1, PTPRD, MAP2K5, SKOR1, and TOX3 [41-44].Together, the allelic variants implicating these six genes account for nearly 50-80% of the population attributable risk for RLS [42, 44, 45].
Imaging studies
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Conventional brain magnetic resonance imaging (MRI) does not show any structural abnormalities in idiopathic RLS patients. Studies of structural brain images using voxel-based morphometry (VBM) and diffusion tensor imaging, have reported contrasting results [46-49]. Multiple studies using iron-sensitive sequences of MRI have shown reduced iron content in several regions of the brain [49-51]. A single study using phase imaging showed significantly higher phase values in RLS patients compared with healthy controls at the level of the substantia nigra, thalamus, putamen, and pallidum [52]. Resting-state fMRIs in 25 patients with untreated idiopathic RLS patients showed that RLS patients have reduced thalamic connectivity with the right parahippocampal gyrus, right precuneus, right precentral gyrus, and bilateral lingual gyri, but increased connectivity with the right superior temporal gyrus, bilateral middle temporal gyrus, and right medial frontal gyrus [53]. The abnormal thalamic connectivity in RLS provides support for impaired processing of sensory information in RLS, further evidence that RLS is a disorder of sensory-motor integration [3]. Functional imaging studies suggest increased striatal synaptic dopamine in RLS. This is supported by findings of lower dopamine-2 receptor binding potentials in putamen and caudate and a significant increase at night in the ventral striatum suggestive of an increase in presynaptic dopaminergic activity [54]. Pathogenesis It has long been observed that iron deficiency exacerbates RLS and iron replacement improves symptoms [55] and brain iron dysregulation is considered to play a key role in the pathogenesis of RLS [56, 57]. Various studies based on analysis of cerebrospinal fluid (CSF) [58, 59], brain MRI [51] and autopsy examinations [60] have shown low levels of iron in the brain of RLS patients. Indeed, dysregulation of iron transport across blood-brain barrier is thought to be the
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chief mechanism of the low brain iron [56]. It has been postulated that the endothelial cells of the blood–brain barrier subserve as an iron reservoir for the brain and that the underlying problem in RLS is the lack of sufficient iron in reserve in the endothelial cells to meet physiological demands [56]. The circadian changes in brain iron status appear to be an important factor in RLS. The level of CSF ferritin, the primary determinant of brain iron status, has been found to be significantly decreased in patients with RLS compared with controls [61]. In the same study the nighttime CSF ferritin levels were lower in the RLS group compared with control subjects, who showed little difference between the 10 am and 10 pm samples. These findings suggest a distinct diurnal variation in CSF iron regulation. Patients with younger-age at onset had significantly lower CSF ferritin levels compared with late-onset group [61]. Tyrosine hydroxylase which is the rate limiting step in dopamine synthesis depends heavily on iron as a cofactor and the low brain iron levels are thought to play a key role in abnormal brain dopamine metabolism in RLS. RLS, therefore, appears to be a disorder of sensory-motor integration [2-4] caused by brain iron dysregulation, leading to secondary changes in dopamine metabolism [57, 62]. This is in contrast to the traditional notion of RLS as a primary disorder of dopamine metabolism. Furthermore, the three major secondary forms of RLS, iron deficiency anemia, end-stage renal disease, and pregnancy, all shares iron deficiency status. Assessment Currently there is no highly specific or sensitive objective biomarker of RLS and there is a need for an instrument that reliably measures and objectively assesses its severity. The overwhelmingly subjective nature of the disorder poses a challenge in documenting change in response to therapeutic interventions. There is also a very high placebo response in RLS [6365]. Multiple scales and questionnaires have been used, but the most commonly used scales to
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assess severity of RLS include the International Restless Legs scale (IRLS) developed by the IRLSSG [66], the Clinical Global Impression (CGI) scale, the RLS-6 scale [67] and the Johns Hopkins Severity Scale [68]. The IRLS severity scale is considered “the gold standard” for assessing the severity of the disorder and consists of 10 questions [69, 70]. The answer to each can be graded into five severity categories ranging from 0 to 4, and, therefore, the maximum total score is 40. Generally, an IRLS score between 1 and 10 is considered mild, between 11 and 20 moderate, between 21 and 30 severe, and between 31 and 40 very severe RLS [66].
Treatment options in RLS Non-pharmacological measures Only few studies have examined the effects of non-pharmacological therapies, such as exercise and good sleep hygiene (e.g. avoiding day time naps and maintaining regular bedtimes). Participating in aerobic and resistance training exercises have been shown to reduce RLS symptoms [71]. One randomized controlled trial showed that by engaging in lower body resistance training and walking on treadmill for 30 minutes three times a week improved RLS symptoms [71]. Although controlled studies are lacking, alcohol, caffeine and nicotine are thought to exacerbate RLS, and therefore, advised to avoid them [72]. Other measures that have been found to be useful in small studies include pneumatic compression devices [73], acupuncture [74] and near infrared light [75]. Tactile and temperature stimulation, including massage or hot baths, can also be successful in temporarily decreasing symptoms, however there is a paucity of rigorously conducted trials confirming their efficacy [76]. The US Food and Drug Administration (FDA) has recently approved the first device to improve sleep in patients with
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RLS. The pad, called Relaxis, provides vibrational counterstimulation to provide external stimulus to the legs (http://dev.sensorymedical.com).
Pharmacological options Dopamine agonists Among the different pharmacological agents, dopamine agonists (DA) are the most widely used [17, 77]. These drugs reduce not only the primary symptoms of RLS but also PLMS. A recent Cochrane meta-analysis concluded that non-ergot DA, such as pramipexole, ropinirole and rotigotine, are effective in various aspects of RLS [78]. However, there are no head-to-head studies comparing the three DAs. DAs also markedly improved PLMS compared with placebo and reduced the autonomic activation that accompany PLMS [79].
Dopamine agonists were widely used as first line therapy in RLS, but evidence from long-term studies raises concerns about its potential to worsen RLS, i.e. augmentation (discussed below). In one study only 25% of the community sample of patients treated with dopamine agonists had a good response with no indication of augmentation [80]. The data indicate that long term treatment with dopamine agonist is successful in less than half of the cases [80, 81]. The long term evaluations show major loss of treatment benefit and development of augmentation which is a major limitation of current care. Impulse control disorder such as pathologic gambling, hyper sexuality, and compulsive shopping occurs in 6–17% of patients with RLS who take DAs [82]. Patients and their families should be adequately warned as to the potential development of these symptoms and physicians should inquire about these aberrant behaviors during follow-up visits [83]. Usually the symptoms resolve with dose reduction or discontinuation.
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Among the DAs, ropinirole was the first to be approved both in the United States and in Europe for RLS treatment [84]. Several large controlled studies have demonstrated its efficacy in improving RLS symptoms [85-87]. The starting dose for ropinirole is 0.25 mg and the recommendation is to dose 1-3 hours before bedtime. The dose can be increased to 0.5 mg in 2 days and 1 mg at the end of 1 week. The maximum recommended dose of ropinirole is 4 mg per day and the mean effective daily dose is 2 mg [88]. The minimum effective dose should be used as higher doses increase the risk for augmentation. Common side effects include nausea (25– 50%), headache (7–22%), fatigue (1–19%), dizziness (6–18%), and vomiting (5–11%) [89]. Several studies using extended-release formulations of ropinirole have been completed or are still in progress (https://clinicaltrials.gov/ct2/home).
Pramipexole is efficacious in moderate to severe RLS [90-92]. In one study pramipexole was completely effective in 67% of patients [93]. Another study with a follow-up period of 8 years, pramipexole was found to be completely effective in only 40% of patients, partially effective in 58% and ineffective in 2% [94]. The range of effective dose was increased from 0.38 mg after initial stabilization to 1 mg at the end of the study. A total of 56% reported daytime sleepiness including 10% who experienced irresistible sleep attacks while driving; 10% developed impulse control disorder. Augmentation developed in 42% of patients, after a mean period of 16.5 months [94]. The augmentation rates for pramipexole have been reported to be about 7% for the first year of treatment [81, 95] and increasing at that rate each year for up to 8 years [80] and 10 years [81]. Thus 50% of patients with RLS treated with pramipexole are estimated to experience augmentation after about 10 years of treatment.
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The starting dose for pramipexole is 0.125 mg taken once daily and the official recommendation is to take it 2-3 hours before bedtime. The maximum recommended dose is 0.75 mg and the effective daily dose ranges from 0.25 to 1 mg although little added benefit is evident beyond 0.5 mg [88]. Common side effects include sleepiness (5–56%), nausea (12–25%), and insomnia (7– 16%) [89]. Pramipexole is mainly excreted through the kidneys and the dose needs to be adjusted according to the creatinine clearance, particularly in patients with renal disease, with titration at about 14-day intervals. Because plasma concentrations for both pramipexole and ropinirole peak nearly 2 hours after ingestion, they should be taken 2-3 hours before bedtime or prior to onset of symptoms. Some patients taking one dose with the evening meal and another dose at bedtime, which helps to maintain symptom control throughout the night [1]. There are no studies directly comparing ropinirole with pramipexole, but a meta-analysis suggests a slightly better symptom control and favorable side effect profile with ropinirole [96].
Rotigotine, a highly selective, lipid-soluble, non-ergoline, D3>D2>D1 DA, 5HT1A agonist, is administered via a patch through a constant delivery system [97-102]. In addition to its use in PD, rotigotine has been also approved for the treatment of moderate to severe RLS. In a randomized, double-blinded, placebo-controlled trial rotigotine transdermal patch proved efficacious at dosages 2 and 3 mg/24 hr in alleviating RLS symptoms over a period of 6 months [99]. Rotigotine should be started at 1 mg/24 hours and dosage can be increased weekly by 1 mg/24 hours and the highest recommended dose is 3 mg/24 hours. In a retrospective review of double-blind, placebo-controlled and open-label studies involving 748 patients treated with rotigotine for up to 1.5 years with RLS, 8.2 % met the diagnostic criteria for augmentation but
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none discontinued the study prematurely due to augmentation [103]. This suggests that the rate of augmentation may be less compared to other DAs. Common side effects include applicationsite skin reaction to the patch (22–58%), nausea (7–19%), headache (4.1–10.8%), and fatigue (0.5–11%)[89]. Since rotigotine patch provides therapeutic plasma levels over 24 hour period, it is a good option in those patients with severe daytime symptoms. In one open label study involving 185 patients with RLS treated with rotigotine for 52 weeks clinically significant augmentation occurred in only five (2.7%) patients [104]. Rotigotine patch is a useful alternative to oral DAs for patients with moderate to severe RLS who are unable to take oral medications (e.g. because of pending surgery) [105].
Cabergoline and pergolide are two ergot dopamine agonists that have been shown to be effective in the treatment of RLS [80, 81]. Cabergoline is effective and well-tolerated as a single evening dose for short-term therapy [106]. Pergolide was shown to substantially improve periodic limb movement measures and subjective sleep disturbance associated with RLS [107]. These two DAs, however, should no longer be used for the treatment of RLS, because of increased risk of cardiac valvular fibrosis and other fibrotic side effects [108]. If used chronically, in patients with refractory symptoms, require close monitoring for adverse effects [109].
Levodopa Levodopa, in combination with a decarboxylase inhibitor, provides the most rapid relief of symptoms in primary and secondary RLS [110, 111]. One study involving 30 patients with RLS 26 (86.7%) continued to benefit from levodopa after two years without loss of efficacy, 9 required dose escalation and two had a complete loss of effect [112]. In another study, however,
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22 of 30 (82.0%) levodopa treated RLS patients, reported symptom augmentation in the late afternoon and evening, resulting in medication withdrawal in 15 (50%) patients [113]. The symptom augmentation consisted of increased severity (100%), shorter onset time to symptoms at rest (56%) and spread of anatomic involvement (11%). While some studies found that only 10% of patients on levodopa discontinued treatment prematurely due to augmentation [114, 115], most studies have concluded that levodopa treatment is associated with a high risk for tolerance, symptom augmentation, and late night or early morning rebound symptoms. The most frequent reasons for premature discontinuation in all the prospective studies were loss of efficacy, adverse effects and augmentation [89]. While levodopa may be helpful when used sparingly as needed in patients with infrequent symptoms, it should be avoided as a chronic treatment in patients with RLS.
Calcium channel alpha-2-delta (α2δ) ligands Currently there are three α2δ ligands used in the treatment of RLS: gabapentin, gabapentin enacarbil and pregabalin. Gabapentin is a gamma aminobutyric acid (GABA) analog but despite its structural similarity to GABA it does not interact directly with GABA receptors. Instead, it binds with high affinity α2δ subunit of the voltage-activated calcium channels [116, 117] and inhibits the calcium currents via high-voltageactivated channels containing the α2δ-1 subunit, leading in turn to reduced neurotransmitter release and attenuation of postsynaptic excitability [118]. In contrast to dopamine agonists, α2δ ligands do not cause augmentation or impulse control disorder and are, therefore, favored as first-line treatment of RLS. Gabapentin is also particularly useful in patients with painful RLS or RLS associated polyneuropathy [119, 120]. Gabapentin also improved sleep initiation and sleep maintenance, to a greater extent than ropinirole [121]. A six weeks double-blind, cross-over
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study involving 24 patients was associated with reduced symptoms on all rating scales, reduced PLMS index and improved sleep architecture with gabapentin compared to placebo. In this study the mean effective dosage at the end of the 6-week treatment period was 1,855 mg (range 6002400 mg) [122].
The side effects are dose dependent but generally mild to moderate in nature, and include dizziness, somnolence, and peripheral edema. Gabapentin 300 mg may be given 2 to 3 hours before bedtime or before the onset of symptoms. A smaller dose may be initiated in the elderly. Dose is increased on a weekly basis until symptoms improve and a maximum dose of 900–2000 mg per dose is reached. Additional doses can be given earlier in the day when troublesome daytime symptoms occur. Dose should be adjusted in patients with renal impairment based on their creatinine clearance. Variable bioavailability due to poor absorption from the gastrointestinal tract and short half-life limit the clinical effectiveness of gabapentin. In April 2011, the US Food and Drug Administration (FDA) approved gabapentin enacarbil, a prodrug of gabapentin, for the treatment of moderate to severe primary RLS in adults [123-133]. Gabapentin enarcorbil was developed in an attempt to address the pharmacokinetic limitations of gabapentin. The pharmacokinetic properties of gabapentin enacarbil allow for once daily administration, typically taken as a 600 mg tablet with food at about 5 pm. At present, a multicenter randomized, double-blind, placebo-controlled clinical trial is being conducted in the United States to compare the efficacy and safety of gabapentin enacarbil at lower doses (450 and 300 mg/day) [134]. Doses higher than 600 mg were thought to provide no additional benefits and increase the chance of adverse reactions. However, the results of post hoc meta-analyses have
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indicated that the 1,200 mg once-daily dosage was effective not only in relieving subjective RLS symptoms but also severe sleep disturbance associated with RLS [135].
Pregabalin, a gabapentin analog, has been found to be effective in the treatment of RLS in double-blind, randomized, controlled studies lasting 6–12 weeks [136-138]. One controlled trial evaluated the efficacy and augmentation in patients with RLS who were treated with pregabalin as compared with placebo and pramipexole [95]. 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. Augmentation rate of 6.6 to 9.0% was seen with pramipexole but only 1.7% with pregabalin over a 52-week period [95]. This study demonstrated that pregabalin compared to pramipexole does not have the long-term complication of augmentation and, additionally, pregabalin was more effective compared to pramipexole 0.25mg (but not 0.5 mg) dose. Although pregabalin was associated with higher rates of suicidal ideation, dizziness, somnolence, and weight gain compared to pramipexole during the early treatment phase, once tolerated it has a lower risk of augmentation and, therefore, favored as first-line agent in the treatment of RLS [95, 139].
Opioids Opioids have long been used in the treatment of RLS. Although concerns about chronic narcotic use have limited their more widespread use, current data shows its effectiveness in those who have failed other therapy [140, 141]. Some support for the role of opioid system in the pathophysiology of RLS was provided by a study which utilized PET scans and
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[11C]diprenorphine, a non-selective opioid receptor radioligand, found that patients with severe the RLS had a robust release of endogenous opioids within the medial thalamic pain system. [142]. A study of beta endorphin, met-enkephalin and leu-enkephalin levels in thalamus and substantia nigra of RLS patients concluded that the endogenous opioids were decreased in the sensory pathways but not the motor pathways of the brains in RLS patients compared to controls [143]. The data supports the possibility that the endogenous opioid system is altered in RLS patients and is consistent with the observation that opioids are involved in the modulation of sensory rather than motor activity.
Low-potency opioids such as codeine, pentazocine, meperidine or medium-potency opioids such as hydrocodone or tramadol [144, 145], can be used for intermittent mild RLS and also for breakthrough symptoms in those with daily RLS. One randomized double-blind study demonstrated that oxycodone is quite effective in suppressing the symptoms of RLS [146]. Also, propoxyphene has been found to be effective in the treatment of PLMS [147].
Opioids can be an excellent choice for patients who have failed other classes of drugs. Although typically not used as first-line therapy opioids can be used in combination with α2δ ligands, DAs or even as monotherapy. One long-term study found that 20 of 36 ( 67 %) patients with RLS who had ever tried opioids as a monotherapy continue this therapy after an average of 5 years and 11 months, with a range of 1–23 years [148]. Addiction and tolerance were encountered in only 1 of the 36 patients on monotherapy, but some had increased sleep apnea [148]. A double blind randomized trial using prolonged release oxycodone–naloxone (132 to prolonged release oxycodone–naloxone vs 144 to placebo) was efficacious for short-term treatment of patients with
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severe RLS inadequately controlled with previous treatment [141]. There were no cases of augmentation. The mean IRLS rating scale sum score decreased from 31.6 (SD 4.5) to –16.5 (SD 11.3) after 12 weeks in the prolonged release oxycodone–naloxone group and –9.4 (SD 10.9) in the placebo group (mean difference between groups at 12 weeks 8.15, 95% CI 5.46–10.85; p
S1389-9457(15)00647-4 http://dx.doi.org/doi:10.1016/j.sleep.2015.03.002 SLEEP 2708
To appear in:
Sleep Medicine
Received date: Revised date: Accepted date:
27-3-2014 28-2-2015 2-3-2015
Please cite this article as: Subhashie Wijemanne, Joseph Jankovic, Restless legs syndrome: Clinical presentation, diagnosis and treatment, Sleep Medicine (2015), http://dx.doi.org/doi:10.1016/j.sleep.2015.03.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Restless Legs Syndrome: Clinical Presentation, Diagnosis and Treatment Subhashie Wijemanne, MD, MRCP, Joseph Jankovic, MD Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas, USA
Address correspondence to:
Joseph Jankovic, MD Professor of Neurology, Distinguished Chair in Movement Disorders, Director of Parkinson’s Disease Center and Movement Disorders Clinic Department of Neurology Baylor College of Medicine 6550 Fannin, Suite 1801 Houston, Texas 77030 Tel: 713-798-5998 Fax: 713-798-6808 Email: [email protected] Web: www.jankovic.org
Highlights
Restless legs syndrome (RLS) is a circadian disorder of sensory-motor integration Augmentation is a major therapy related complication of dopaminergic medications α2δ ligands such as gabapentin are favored over dopamine agonist as first-line agents
1 Page 1 of 48
Opioids can be used as monotherapy or in combination in refractory RLS
Abstract Restless legs syndrome (RLS) is a circadian disorder of sensory-motor integration which may be related to genetically-determined dysregulation of iron transport across the blood brain barrier. Dopamine agonists (DA) have been considered the first line therapy but with the growing appreciation of problems associated with long-term treatment, particularly augmentation and impulse control disorder, alpha-2-delta drugs, such as gabapentin, are now considered the first line of treatment in patients with troublesome RLS. Opioids can be considered as alternative therapy, particularly in patients with DA-related augmentation. In more severe cases, combination therapy may be required. Intravenous iron therapy may be considered on those patients with refractory RLS.
Keywords Restless legs syndrome, augmentation, dopamine agonist, pramipexole, ropinirole, rotigotine, methadone, gabapentin
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Introduction Restless legs syndrome (RLS), also referred to as Willis-Ekbom disease (WED), is a chronic neurological disorder that may require lifelong treatment [1]. Majority of patients with RLS respond well to currently available medications. One of the most challenging aspects of treating RLS is the occurrence of medication related complication namely augmentation (discussed in more detail below) and its management. A subset of patients’ may also progress to severe or refractory RLS (“malignant RLS”) which can be very disabling. This article summarizes different clinical presentations, diagnosis of RLS with an emphasis on management of RLS.
RLS is a circadian disorder of sensory-motor integration manifested by an urge or a need to move the limbs to stop unpleasant sensations in the evening or while at rest [1-4]. First described by Thomas Willis in 1685, it was Ekbom in 1945, who described essentially all the cardinal clinical features of the syndrome and coined the name “restless legs syndrome” [5]. In recognition of the contributions by these two pioneers, the nonprofit Restless Legs Syndrome Foundation was recently renamed as the Willis-Ekbom Disease Foundation [6].
The diagnosis of RLS is based on the 2012 revised International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria [7, 8]. Compared to the 2003 criteria, the 2012 version
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includes a 5th criteria to rule out RLS mimickers [9] and in addition, all the essential diagnostic criteria have to be met: 1) The urge to move the legs, usually but not always accompanied by or felt to be caused by uncomfortable and unpleasant sensations in the legs; 2) The urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting; 3) The urge to move the legs and any accompanying unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues; 4) The urge to move and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night than during the day; 5) The above features are not solely accounted for by other medical or behavioral conditions, such as myalgias, venous stasis, leg edema, arthritis, leg cramps [10], positional discomfort, habitual foot tapping, and other nocturnal sensory-motor symptoms.
Clinical Manifestations Descriptions of the uncomfortable sensation (in descending order of frequency) include: "need to move", "crawling", "tingling", "restless", “cramping”, “creeping", "pulling", "painful", "electric", "tension", "itching", “burning”, “prickly”, but unique, culturally-determined, terms such as “heebie jeebies", “wriggling magots”, “elvis legs”, “the shpilke”, and others [11, 12]. Typical RLS sensations are felt deep inside the muscles and bones of the legs but some patients describe sensations that are felt superficially in the skin [11]. In one study, 28 of 44 (64%) of patients had predominantly bilateral leg symptoms and 15 of 44 (34%) had predominantly unilateral symptoms; upper calf was the most frequently affected region (73%) [13]. As RLS progresses the symptoms may no longer be confined to the legs and may progress to the arms [13]. Akathisia is an abnormal state of excessive restlessness with an urge or the need to move but,
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unlike RLS, it is much more generalized and it does not have diurnal variation [3, 14]. The newly described, although very common, “leg stereotypy disorder”, is manifested by stereotypic, 1-2 Hz rhythmical, flexion-extension and abduction-adduction movements of the hips and flexionextension movements of the ankles while the individual is sitting with the toes of the foot pressed against the floor or when the legs are crossed [3]. In situations where the diagnosis is uncertain, the levodopa test (50% improvement in symptoms after 25/100 mg of carbidopa/levodopa) might be useful [15], but it should be noted that in clinical trials 15 - 40% did not respond to dopaminergic drugs. In addition to primary RLS, secondary causes of RLS include iron deficiency, pregnancy and end-stage renal disease. Neuropathy may be associated with RLS-like symptoms but usually without diurnal variation and typically accompanied by other neurological symptoms and deficits including sensory, motor and reflex abnormalities. Periodic limb movements of sleep (PLMS), present in over 80%-90% of RLS patients [16], consists of highly stereotyped movements that typically involve extension of the big toe with partial flexion of the ankle, knee, and sometimes the hip (“triple flexion”) and occasionally in the upper extremities [17]. Movements are usually bilateral but are not necessarily symmetrical or synchronous; they may predominate in one leg or alternate between legs. PLMS can occur in the upper extremities and is often manifested as repetitive flexion at the elbow. The duration of movement is typically between 1.5-2.5 seconds with a periodicity of between 20 and 40 seconds, although wide ranges of frequencies have been reported. Periodic limb movements can occur during wakefulness and are referred to as “periodic limb movements while awake” (PLMW) [18]. These are typically jerk-like movements with an appearance and distribution similar to PLMS, but with greater intensity and speed [18]. Periodic limb movements of sleep index
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(PLMSI), number of leg movements per hour, is one of the measures recorded by polysomnography (PSG). Specific criteria for recording and scoring periodic leg movements can be found in World Association of Sleep Medicine criteria [19]. Quantification of PLMS is currently used as an objective measure of assessing RLS [20]. However, the presence of PLMS is not essential to make a diagnosis of RLS and, therefore, an overnight PSG is not necessary for the diagnosis of RLS. The impact of RLS on sleep, particularly sleep-onset insomnia [21], contributes to the overall adverse impact on quality of life, often leading to serious psychosocial impairment [22, 23]. Disturbed sleep is usually the primary reason a patient seeks medical attention. Additionally, there is also a strong association between untreated RLS and depression [24]. With increasing disease severity and prominent sleep disruption, the circadian pattern can be overridden and symptoms may be present 24 hours a day [25]. Although it is well recognized that patients with RLS associated with renal disease have a higher mortality [26], there is some controversy whether patients with idiopathic RLS [27] also have a higher overall mortality [23]. One study reported an adjusted mortality hazard ratio of 1.92 (95% CI 1.03-3.56; p = 0.04, attributed to a variety of medical problems, but further studies are needed to confirm this observation [28].
Epidemiology Based on well conducted epidemiological studies the overall prevalence of RLS has been reported to range from 7% for any RLS to 2.7% for clinically apparent RLS [29]. For primary RLS (excluding secondary causes) the overall prevalence in the USA was estimated to be 2.4% and 1.5% for primary and clinically significant RLS [23]. RLS seems to be an age-related
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disorders, although symptoms can begin in childhood, and 38% of adults have reported the onset of symptoms before the ages of 20 years and 10% before the age of 10 years [16]. The overall prevalence of gender-adjusted primary RLS in the United States was estimated to be 2.4%, increasing with age from 1.4% (for ages 20–29) to 3.3% (for ages 60–69) and then decreasing to 1.7% for the oldest age group [23]. Studies from non-European countries show a relatively lower prevalence: 0.1% in Singapore [30], 0.9% in South Korea [31]. Females are affected twice as frequently as males across all population groups and ages [32]. However, RLS continues to remain grossly under-diagnosed [29, 33]. The relationship between RLS and Parkinson’s disease (PD) is controversial. Some studies have shown that up to 20% of patients with PD have RLS [34-37] but the preponderance of data suggests that RLS is not a risk factor for the eventual development of PD [38].
Genetics The presence of family history in RLS is common and when present, supports the diagnosis of RLS.Primary RLS is characterized by high familial aggregation suggesting a genetic component. Approximately 63% of patients report having at least one first-degree relative with the condition [16]. Despite intensive efforts, a monogenic cause for RLS has not been detected to date [39, 40]. Independent genome-wide association studies in diverse populations of Northern European origin have found six different genes that may play a role in RLS: BTBD9, MEIS1, PTPRD, MAP2K5, SKOR1, and TOX3 [41-44].Together, the allelic variants implicating these six genes account for nearly 50-80% of the population attributable risk for RLS [42, 44, 45].
Imaging studies
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Conventional brain magnetic resonance imaging (MRI) does not show any structural abnormalities in idiopathic RLS patients. Studies of structural brain images using voxel-based morphometry (VBM) and diffusion tensor imaging, have reported contrasting results [46-49]. Multiple studies using iron-sensitive sequences of MRI have shown reduced iron content in several regions of the brain [49-51]. A single study using phase imaging showed significantly higher phase values in RLS patients compared with healthy controls at the level of the substantia nigra, thalamus, putamen, and pallidum [52]. Resting-state fMRIs in 25 patients with untreated idiopathic RLS patients showed that RLS patients have reduced thalamic connectivity with the right parahippocampal gyrus, right precuneus, right precentral gyrus, and bilateral lingual gyri, but increased connectivity with the right superior temporal gyrus, bilateral middle temporal gyrus, and right medial frontal gyrus [53]. The abnormal thalamic connectivity in RLS provides support for impaired processing of sensory information in RLS, further evidence that RLS is a disorder of sensory-motor integration [3]. Functional imaging studies suggest increased striatal synaptic dopamine in RLS. This is supported by findings of lower dopamine-2 receptor binding potentials in putamen and caudate and a significant increase at night in the ventral striatum suggestive of an increase in presynaptic dopaminergic activity [54]. Pathogenesis It has long been observed that iron deficiency exacerbates RLS and iron replacement improves symptoms [55] and brain iron dysregulation is considered to play a key role in the pathogenesis of RLS [56, 57]. Various studies based on analysis of cerebrospinal fluid (CSF) [58, 59], brain MRI [51] and autopsy examinations [60] have shown low levels of iron in the brain of RLS patients. Indeed, dysregulation of iron transport across blood-brain barrier is thought to be the
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chief mechanism of the low brain iron [56]. It has been postulated that the endothelial cells of the blood–brain barrier subserve as an iron reservoir for the brain and that the underlying problem in RLS is the lack of sufficient iron in reserve in the endothelial cells to meet physiological demands [56]. The circadian changes in brain iron status appear to be an important factor in RLS. The level of CSF ferritin, the primary determinant of brain iron status, has been found to be significantly decreased in patients with RLS compared with controls [61]. In the same study the nighttime CSF ferritin levels were lower in the RLS group compared with control subjects, who showed little difference between the 10 am and 10 pm samples. These findings suggest a distinct diurnal variation in CSF iron regulation. Patients with younger-age at onset had significantly lower CSF ferritin levels compared with late-onset group [61]. Tyrosine hydroxylase which is the rate limiting step in dopamine synthesis depends heavily on iron as a cofactor and the low brain iron levels are thought to play a key role in abnormal brain dopamine metabolism in RLS. RLS, therefore, appears to be a disorder of sensory-motor integration [2-4] caused by brain iron dysregulation, leading to secondary changes in dopamine metabolism [57, 62]. This is in contrast to the traditional notion of RLS as a primary disorder of dopamine metabolism. Furthermore, the three major secondary forms of RLS, iron deficiency anemia, end-stage renal disease, and pregnancy, all shares iron deficiency status. Assessment Currently there is no highly specific or sensitive objective biomarker of RLS and there is a need for an instrument that reliably measures and objectively assesses its severity. The overwhelmingly subjective nature of the disorder poses a challenge in documenting change in response to therapeutic interventions. There is also a very high placebo response in RLS [6365]. Multiple scales and questionnaires have been used, but the most commonly used scales to
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assess severity of RLS include the International Restless Legs scale (IRLS) developed by the IRLSSG [66], the Clinical Global Impression (CGI) scale, the RLS-6 scale [67] and the Johns Hopkins Severity Scale [68]. The IRLS severity scale is considered “the gold standard” for assessing the severity of the disorder and consists of 10 questions [69, 70]. The answer to each can be graded into five severity categories ranging from 0 to 4, and, therefore, the maximum total score is 40. Generally, an IRLS score between 1 and 10 is considered mild, between 11 and 20 moderate, between 21 and 30 severe, and between 31 and 40 very severe RLS [66].
Treatment options in RLS Non-pharmacological measures Only few studies have examined the effects of non-pharmacological therapies, such as exercise and good sleep hygiene (e.g. avoiding day time naps and maintaining regular bedtimes). Participating in aerobic and resistance training exercises have been shown to reduce RLS symptoms [71]. One randomized controlled trial showed that by engaging in lower body resistance training and walking on treadmill for 30 minutes three times a week improved RLS symptoms [71]. Although controlled studies are lacking, alcohol, caffeine and nicotine are thought to exacerbate RLS, and therefore, advised to avoid them [72]. Other measures that have been found to be useful in small studies include pneumatic compression devices [73], acupuncture [74] and near infrared light [75]. Tactile and temperature stimulation, including massage or hot baths, can also be successful in temporarily decreasing symptoms, however there is a paucity of rigorously conducted trials confirming their efficacy [76]. The US Food and Drug Administration (FDA) has recently approved the first device to improve sleep in patients with
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RLS. The pad, called Relaxis, provides vibrational counterstimulation to provide external stimulus to the legs (http://dev.sensorymedical.com).
Pharmacological options Dopamine agonists Among the different pharmacological agents, dopamine agonists (DA) are the most widely used [17, 77]. These drugs reduce not only the primary symptoms of RLS but also PLMS. A recent Cochrane meta-analysis concluded that non-ergot DA, such as pramipexole, ropinirole and rotigotine, are effective in various aspects of RLS [78]. However, there are no head-to-head studies comparing the three DAs. DAs also markedly improved PLMS compared with placebo and reduced the autonomic activation that accompany PLMS [79].
Dopamine agonists were widely used as first line therapy in RLS, but evidence from long-term studies raises concerns about its potential to worsen RLS, i.e. augmentation (discussed below). In one study only 25% of the community sample of patients treated with dopamine agonists had a good response with no indication of augmentation [80]. The data indicate that long term treatment with dopamine agonist is successful in less than half of the cases [80, 81]. The long term evaluations show major loss of treatment benefit and development of augmentation which is a major limitation of current care. Impulse control disorder such as pathologic gambling, hyper sexuality, and compulsive shopping occurs in 6–17% of patients with RLS who take DAs [82]. Patients and their families should be adequately warned as to the potential development of these symptoms and physicians should inquire about these aberrant behaviors during follow-up visits [83]. Usually the symptoms resolve with dose reduction or discontinuation.
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Among the DAs, ropinirole was the first to be approved both in the United States and in Europe for RLS treatment [84]. Several large controlled studies have demonstrated its efficacy in improving RLS symptoms [85-87]. The starting dose for ropinirole is 0.25 mg and the recommendation is to dose 1-3 hours before bedtime. The dose can be increased to 0.5 mg in 2 days and 1 mg at the end of 1 week. The maximum recommended dose of ropinirole is 4 mg per day and the mean effective daily dose is 2 mg [88]. The minimum effective dose should be used as higher doses increase the risk for augmentation. Common side effects include nausea (25– 50%), headache (7–22%), fatigue (1–19%), dizziness (6–18%), and vomiting (5–11%) [89]. Several studies using extended-release formulations of ropinirole have been completed or are still in progress (https://clinicaltrials.gov/ct2/home).
Pramipexole is efficacious in moderate to severe RLS [90-92]. In one study pramipexole was completely effective in 67% of patients [93]. Another study with a follow-up period of 8 years, pramipexole was found to be completely effective in only 40% of patients, partially effective in 58% and ineffective in 2% [94]. The range of effective dose was increased from 0.38 mg after initial stabilization to 1 mg at the end of the study. A total of 56% reported daytime sleepiness including 10% who experienced irresistible sleep attacks while driving; 10% developed impulse control disorder. Augmentation developed in 42% of patients, after a mean period of 16.5 months [94]. The augmentation rates for pramipexole have been reported to be about 7% for the first year of treatment [81, 95] and increasing at that rate each year for up to 8 years [80] and 10 years [81]. Thus 50% of patients with RLS treated with pramipexole are estimated to experience augmentation after about 10 years of treatment.
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The starting dose for pramipexole is 0.125 mg taken once daily and the official recommendation is to take it 2-3 hours before bedtime. The maximum recommended dose is 0.75 mg and the effective daily dose ranges from 0.25 to 1 mg although little added benefit is evident beyond 0.5 mg [88]. Common side effects include sleepiness (5–56%), nausea (12–25%), and insomnia (7– 16%) [89]. Pramipexole is mainly excreted through the kidneys and the dose needs to be adjusted according to the creatinine clearance, particularly in patients with renal disease, with titration at about 14-day intervals. Because plasma concentrations for both pramipexole and ropinirole peak nearly 2 hours after ingestion, they should be taken 2-3 hours before bedtime or prior to onset of symptoms. Some patients taking one dose with the evening meal and another dose at bedtime, which helps to maintain symptom control throughout the night [1]. There are no studies directly comparing ropinirole with pramipexole, but a meta-analysis suggests a slightly better symptom control and favorable side effect profile with ropinirole [96].
Rotigotine, a highly selective, lipid-soluble, non-ergoline, D3>D2>D1 DA, 5HT1A agonist, is administered via a patch through a constant delivery system [97-102]. In addition to its use in PD, rotigotine has been also approved for the treatment of moderate to severe RLS. In a randomized, double-blinded, placebo-controlled trial rotigotine transdermal patch proved efficacious at dosages 2 and 3 mg/24 hr in alleviating RLS symptoms over a period of 6 months [99]. Rotigotine should be started at 1 mg/24 hours and dosage can be increased weekly by 1 mg/24 hours and the highest recommended dose is 3 mg/24 hours. In a retrospective review of double-blind, placebo-controlled and open-label studies involving 748 patients treated with rotigotine for up to 1.5 years with RLS, 8.2 % met the diagnostic criteria for augmentation but
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none discontinued the study prematurely due to augmentation [103]. This suggests that the rate of augmentation may be less compared to other DAs. Common side effects include applicationsite skin reaction to the patch (22–58%), nausea (7–19%), headache (4.1–10.8%), and fatigue (0.5–11%)[89]. Since rotigotine patch provides therapeutic plasma levels over 24 hour period, it is a good option in those patients with severe daytime symptoms. In one open label study involving 185 patients with RLS treated with rotigotine for 52 weeks clinically significant augmentation occurred in only five (2.7%) patients [104]. Rotigotine patch is a useful alternative to oral DAs for patients with moderate to severe RLS who are unable to take oral medications (e.g. because of pending surgery) [105].
Cabergoline and pergolide are two ergot dopamine agonists that have been shown to be effective in the treatment of RLS [80, 81]. Cabergoline is effective and well-tolerated as a single evening dose for short-term therapy [106]. Pergolide was shown to substantially improve periodic limb movement measures and subjective sleep disturbance associated with RLS [107]. These two DAs, however, should no longer be used for the treatment of RLS, because of increased risk of cardiac valvular fibrosis and other fibrotic side effects [108]. If used chronically, in patients with refractory symptoms, require close monitoring for adverse effects [109].
Levodopa Levodopa, in combination with a decarboxylase inhibitor, provides the most rapid relief of symptoms in primary and secondary RLS [110, 111]. One study involving 30 patients with RLS 26 (86.7%) continued to benefit from levodopa after two years without loss of efficacy, 9 required dose escalation and two had a complete loss of effect [112]. In another study, however,
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22 of 30 (82.0%) levodopa treated RLS patients, reported symptom augmentation in the late afternoon and evening, resulting in medication withdrawal in 15 (50%) patients [113]. The symptom augmentation consisted of increased severity (100%), shorter onset time to symptoms at rest (56%) and spread of anatomic involvement (11%). While some studies found that only 10% of patients on levodopa discontinued treatment prematurely due to augmentation [114, 115], most studies have concluded that levodopa treatment is associated with a high risk for tolerance, symptom augmentation, and late night or early morning rebound symptoms. The most frequent reasons for premature discontinuation in all the prospective studies were loss of efficacy, adverse effects and augmentation [89]. While levodopa may be helpful when used sparingly as needed in patients with infrequent symptoms, it should be avoided as a chronic treatment in patients with RLS.
Calcium channel alpha-2-delta (α2δ) ligands Currently there are three α2δ ligands used in the treatment of RLS: gabapentin, gabapentin enacarbil and pregabalin. Gabapentin is a gamma aminobutyric acid (GABA) analog but despite its structural similarity to GABA it does not interact directly with GABA receptors. Instead, it binds with high affinity α2δ subunit of the voltage-activated calcium channels [116, 117] and inhibits the calcium currents via high-voltageactivated channels containing the α2δ-1 subunit, leading in turn to reduced neurotransmitter release and attenuation of postsynaptic excitability [118]. In contrast to dopamine agonists, α2δ ligands do not cause augmentation or impulse control disorder and are, therefore, favored as first-line treatment of RLS. Gabapentin is also particularly useful in patients with painful RLS or RLS associated polyneuropathy [119, 120]. Gabapentin also improved sleep initiation and sleep maintenance, to a greater extent than ropinirole [121]. A six weeks double-blind, cross-over
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study involving 24 patients was associated with reduced symptoms on all rating scales, reduced PLMS index and improved sleep architecture with gabapentin compared to placebo. In this study the mean effective dosage at the end of the 6-week treatment period was 1,855 mg (range 6002400 mg) [122].
The side effects are dose dependent but generally mild to moderate in nature, and include dizziness, somnolence, and peripheral edema. Gabapentin 300 mg may be given 2 to 3 hours before bedtime or before the onset of symptoms. A smaller dose may be initiated in the elderly. Dose is increased on a weekly basis until symptoms improve and a maximum dose of 900–2000 mg per dose is reached. Additional doses can be given earlier in the day when troublesome daytime symptoms occur. Dose should be adjusted in patients with renal impairment based on their creatinine clearance. Variable bioavailability due to poor absorption from the gastrointestinal tract and short half-life limit the clinical effectiveness of gabapentin. In April 2011, the US Food and Drug Administration (FDA) approved gabapentin enacarbil, a prodrug of gabapentin, for the treatment of moderate to severe primary RLS in adults [123-133]. Gabapentin enarcorbil was developed in an attempt to address the pharmacokinetic limitations of gabapentin. The pharmacokinetic properties of gabapentin enacarbil allow for once daily administration, typically taken as a 600 mg tablet with food at about 5 pm. At present, a multicenter randomized, double-blind, placebo-controlled clinical trial is being conducted in the United States to compare the efficacy and safety of gabapentin enacarbil at lower doses (450 and 300 mg/day) [134]. Doses higher than 600 mg were thought to provide no additional benefits and increase the chance of adverse reactions. However, the results of post hoc meta-analyses have
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indicated that the 1,200 mg once-daily dosage was effective not only in relieving subjective RLS symptoms but also severe sleep disturbance associated with RLS [135].
Pregabalin, a gabapentin analog, has been found to be effective in the treatment of RLS in double-blind, randomized, controlled studies lasting 6–12 weeks [136-138]. One controlled trial evaluated the efficacy and augmentation in patients with RLS who were treated with pregabalin as compared with placebo and pramipexole [95]. 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. Augmentation rate of 6.6 to 9.0% was seen with pramipexole but only 1.7% with pregabalin over a 52-week period [95]. This study demonstrated that pregabalin compared to pramipexole does not have the long-term complication of augmentation and, additionally, pregabalin was more effective compared to pramipexole 0.25mg (but not 0.5 mg) dose. Although pregabalin was associated with higher rates of suicidal ideation, dizziness, somnolence, and weight gain compared to pramipexole during the early treatment phase, once tolerated it has a lower risk of augmentation and, therefore, favored as first-line agent in the treatment of RLS [95, 139].
Opioids Opioids have long been used in the treatment of RLS. Although concerns about chronic narcotic use have limited their more widespread use, current data shows its effectiveness in those who have failed other therapy [140, 141]. Some support for the role of opioid system in the pathophysiology of RLS was provided by a study which utilized PET scans and
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[11C]diprenorphine, a non-selective opioid receptor radioligand, found that patients with severe the RLS had a robust release of endogenous opioids within the medial thalamic pain system. [142]. A study of beta endorphin, met-enkephalin and leu-enkephalin levels in thalamus and substantia nigra of RLS patients concluded that the endogenous opioids were decreased in the sensory pathways but not the motor pathways of the brains in RLS patients compared to controls [143]. The data supports the possibility that the endogenous opioid system is altered in RLS patients and is consistent with the observation that opioids are involved in the modulation of sensory rather than motor activity.
Low-potency opioids such as codeine, pentazocine, meperidine or medium-potency opioids such as hydrocodone or tramadol [144, 145], can be used for intermittent mild RLS and also for breakthrough symptoms in those with daily RLS. One randomized double-blind study demonstrated that oxycodone is quite effective in suppressing the symptoms of RLS [146]. Also, propoxyphene has been found to be effective in the treatment of PLMS [147].
Opioids can be an excellent choice for patients who have failed other classes of drugs. Although typically not used as first-line therapy opioids can be used in combination with α2δ ligands, DAs or even as monotherapy. One long-term study found that 20 of 36 ( 67 %) patients with RLS who had ever tried opioids as a monotherapy continue this therapy after an average of 5 years and 11 months, with a range of 1–23 years [148]. Addiction and tolerance were encountered in only 1 of the 36 patients on monotherapy, but some had increased sleep apnea [148]. A double blind randomized trial using prolonged release oxycodone–naloxone (132 to prolonged release oxycodone–naloxone vs 144 to placebo) was efficacious for short-term treatment of patients with
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severe RLS inadequately controlled with previous treatment [141]. There were no cases of augmentation. The mean IRLS rating scale sum score decreased from 31.6 (SD 4.5) to –16.5 (SD 11.3) after 12 weeks in the prolonged release oxycodone–naloxone group and –9.4 (SD 10.9) in the placebo group (mean difference between groups at 12 weeks 8.15, 95% CI 5.46–10.85; p
