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Restless legs syndrome (RLS) is a neurological disorder characterized by an urge to move the legs often accompanied by unpleasant sensations. Symptoms appear during periods of rest or inactivity, particularly in the evening and at night, and are usually relieved by movement. The prevalence of RLS among Whites is approximately 5–15%. RLS can be distinguished into primary and secondary forms. Most patients (70–80%) are affected by the primary form of RLS. The uncomfortable sensations related to RLS often cause a minimal discomfort, thus a therapeutic approach is not necessary. However, almost 3% of the general population reports to be affected by severe symptoms of RLS, requiring pharmacological treatment. Secondary forms of RLS are relieved by the remission of the underlying clinical condition. Dopamine agonists are considered to be first-line treatments for primary RLS. Rotigotine is a nonergoline dopamine agonist with selectivity for D1, D2 and D3 receptors. It is administered once a day in the form of an adhesive matrix patch. The efficacy and safety of the drug in patients with primary RLS has been demonstrated by four clinical trials using dosages of 0.5, 1, 2, 3 and 4mg/24h. A dose–response relationship was observed between the dosages of 0.5 and 3mg/24h. Side effects were usually mild, the most frequent being skin reaction at the site of patch application. More trials are ongoing and results will soon be published for the long-term (5 years) treatment of RLS with rotigotine transdermal patches. Rotigotine is a promising drug for the treatment of RLS. Its continuous delivery throughout 24h makes it especially indicated for those cases also presenting daytime symptoms, and for those presenting the so-called augmentation syndrome after prolonged treatment with L-dopa or dopamine agonists.
Restless legs syndrome (RLS) is a common neurological disorder characterized by an urge to move the legs (sometime also the arms) often accompanied by unpleasant sensations (creeping, crawling, tingling, pulling, pain) [Trenkwalder et al. 2005]. Symptoms appear during periods of rest or inactivity, particularly in the evening and at night, and are usually relieved by movement. RLS is frequently associated with involuntary, rhythmic muscular jerks in the lower limbs: dorsiflexion or fanning of toes, flexion of ankles, knees and hips, so-called periodic limb movements (PLMs), present during sleep (PLMS) or during wakefulness (PLMW) [Provini et al. 2001]. RLS presents a circadian pattern that seems related to the circadian fluctuations of dopaminergic activity, showing a maximum of symptoms from 23:00 to 03:00 and a minimum between 09:00 and 14:00 [Michaud et al. 2004].
The results of physical examination of RLS patients are usually normal and, with the exception of symptomatic secondary forms, objective neurological signs are lacking. RLS has a negative impact on sleep, cognitive function, quality of life (QoL), mental status and cardiovascular functions [Winkelman et al. 2008; Gangwisch et al. 2006].
The prevalence of RLS among Whites is approximately 5–15%. The prevalence of RLS increases in relation to age, and is higher amongst women [Bjorvatn et al. 2005; Berger et al. 2004; Ulfberg et al. 2001]. RLS can be distinguished into idiopathic or primary and symptomatic or secondary forms. A large proportion of patients (70–80%) are affected by the primary form of RLS [Bassetti et al. 2001]. In order to diagnose a primary form of RLS, all those clinical conditions able to cause a secondary form of RLS must be ruled out by means of laboratory, physical, neurological and neurophysiological examinations. Primary RLS is characterized by a positive family history and younger age at onset [Winkelmann et al. 2000]. In fact, a family history consistent with dominant inheritance is present in more than 40% of patients with idiopathic RLS. In addition, patients with an onset of RLS before the age of 45 years have been found to have a significantly higher incidence of affected relatives compared with those who reported symptoms onset later in life (age >45 years). A genetic basis has also been suggested [Winkelmann, 2008]. Linkage studies have demonstrated the presence of various different loci associated with RLS, pointing out the genetic heterogeneity of the sleep disorder.
RLS can occur secondary to a number of disorders including end-stage renal disease [Gigli et al. 2004; Walker et al. 1995], nondialysed patients with chronic renal failure [Merlino et al. 2010], pregnancy [Manconi et al. 2004], hyposideremia [O’Keeffe et al. 1994], diabetes [Merlino et al. 2007], polyneuropathy [Rutkove et al. 1996] and several neurological disorders (such as multiple sclerosis [Manconi et al. 2008]) and has iatrogenic forms. Secondary forms of RLS are characterized by a low frequency of positive family history, a late age at onset of symptoms, the antecedence of onset of the main clinical condition to RLS onset, and, most importantly, the amelioration/disappearance of RLS symptoms following remission of the main clinical condition.
The diagnosis of RLS is based on the presence of four criteria developed by the International Restless Legs Syndrome Study Group (IRLSSG) [Allen et al. 2003], that are: (i) an urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs (sometimes the urge to move is present without the uncomfortable sensations and sometimes the arms or other body parts are involved in addition to the legs); (ii) the urge to move or the unpleasant sensation begins or worsens during periods of rest or inactivity such as lying down or sitting; (iii) the urge to move or the unpleasant sensation is partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues; (iv) the urge to move or the unpleasant sensation is worse in the evening or night (when symptoms are very severe, the worsening at night may not be noticeable, but must have been present previously).
Severity of RLS can be assessed by means of three different severity scales: the International Restless Legs Syndrome rating scale (IRLS) [Walters et al. 2003], the RLS-6 [Kohnen et al. 2004] and the John Hopkins RLS severity scale (JHRLSS) [Allen and Earley, 2001]. The gold standard in evaluating severity of RLS is the IRLS. It consists of 10 items, each graded from 0 to 4. The total score ranges from 0 (no symptoms) to 40 (very severe symptoms). The RLS-6 scale consists of the following items: patients’ rating of severity of RLS (1) at bedtime, (2) during the night, (3) during the day when patients are at rest, and (4) during the day when patients are active (11-point score ranging from 0, symptoms not present, to 10, very severe), (5) patients’ rating of satisfaction with sleep (11-point score ranging from 0, excellent sleep, to 10, extremely bad sleep quality) and (6) patients’ ratings of daytime tiredness (11-point score ranging from 0, not tired, to 10, very severe tiredness). The RLS-6 and the JHRLSS, which consists of only one question, are usually less used in clinical practice to assess RLS severity.
In addition, another scale, the clinical global impression (CGI), used for evaluating severity of diseases in general, can also be applied to RLS. It assesses (1) the severity of RLS symptoms (seven-point score: 1, not at all ill, to 7, extremely ill), (2) global change of condition (1, very much improved, to 7, very much worsened), and (3) therapeutic effect (1, marked, to 4, unchanged or worse).
The precise pathogenesis of RLS is still unknown, but there is evidence from basic science of a dysfunction of diencephalic A11 dopaminergic neurons as the origin of RLS symptoms [Qu et al. 2006; Ondo et al. 2000]. These neurons seem to be able to modulate the nociceptive afferents by means of their projections into the dorsal horns of the spinal cord. Studies conducted on rats have induced features similar to those of human RLS by causing specific lesions in the A11 nuclei. The other evidence that supports this theory is that both idiopathic and secondary RLS show a positive response to dopaminergic treatment, and a negative response during therapy with antidopaminergic treatments [Trenkwalder et al. 2005].
The therapeutic approach to RLS can be divided into nonpharmacological and pharmacological treatment. Often the uncomfortable sensations related to RLS have an inconstant appearance and cause a minimal discomfort, thus a therapeutic approach is not necessary. However, almost 3% of the general population reports to be affected by severe symptoms of RLS, occurring for more than 2 days per week [Hening et al. 2004]. These subjects require a pharmacological treatment. First of all, it is important to rule out causes of secondary RLS (one of the most common is iron deficiency) and to eliminate the triggering factors, if any. Treating the underlying clinical condition may also cause remission of RLS symptoms. For primary RLS, no treatments modifying the course of the disease are available. Therefore, the goal of different therapeutic strategies is the control of symptoms. Nonpharmacological treatment consists of behavioural therapy, sleep hygiene and lifestyle interventions (avoiding caffeine, alcohol, heavy meals and drugs able to induce RLS). This type of approach is not nowadays confirmed by a significant number of studies. To date, the ‘state of the art’ in idiopathic RLS therapy considers dopamine agonists as the first-line treatment. Levo-dopa (L-dopa) also represents a therapeutic approach due to its efficacy in controlling sensory and motor symptoms, although, as a consequence of its short plasma half life, there is a rapidly decreasing effect and RLS may reappear in the second half of the night. L-dopa is generally reserved for patients with mild RLS or intermittent symptoms. Dopamine agonists work at dopamine receptors and, unlike L-dopa, are not metabolized into dopamine. The nonergot-derived dopamine agonists are generally recommended for the treatment of daily RLS; the most frequently used are pramipexole (with a dosage between 0.125 and 0.75mg), ropinirole (0.25–4mg; mean 2mg) and rotigotine. The ergot dopamine agonists are less frequently used for RLS and require special monitoring due to an increased incidence of cardiac valvular fibrosis and other fibrotic side effects. On 29 March 2007 the US Food and Drugs Administration (FDA) withdrew pergolide from the market because of the risk of serious damage to patients’ heart valves. In the same year a study in the New England Journal of Medicine confirmed previous findings associating pergolide with increased chance of regurgitation of the mitral, tricuspid and aortic valves of the heart [Kast and Altschuler, 2007]. Nonergot-derived dopamine agonists have been approved by the FDA for the treatment of RLS.
Augmentation is a common complication of dopaminergic treatment of RLS that is characterized by the following criteria: compared with baseline, RLS symptoms occur earlier during the 24-h day (circadian anticipation), latency to onset of symptoms when at rest is shorter, intensity of symptoms is increased and other body parts may be involved [Garcia-Borreguero et al. 2007]. Augmentation is most frequently observed with L-dopa [Collado-Seidel et al. 1999; Allen and Earley, 1996], in a lower rate with pramipexole [Winkelman and Bennet, 2004], and even less with cabergoline [Stiasny-Kolster et al. 2004a], thus, suggesting that it may be the consequence of the short plasma half life of the drug. Augmentation is more frequent with higher doses and longer treatment duration. Augmentation of symptoms and rebound with ongoing treatment have compromised the utility of L-dopa in RLS patients with daily symptoms. In an algorithm for the treatment of RLS published in 2004, L-dopa was recommended only for the treatment of intermittent RLS, as infrequent use of L-dopa may carry less risk for the development of augmentation.
The chemical name of rotigotine is S-(-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralinhydrochloride. The empirical formula is C19H25NOS. The molecular weight is 315.48 Da.
Rotigotine has a D1–D2–D3 receptors agonistic activity with about 15-fold higher affinity for the D2 receptor than for the D1 receptor. It is also characterized by an antagonistic activity at the α2-adrenergic receptor and agonistic activity at the 5-hydroxytryptamine type 1a and 2 receptors. In addition, at high concentrations (>106mol/l), rotigotine may promote release of norepinephrine [Cawello et al. 2009].
Rotigotine is administered once a day in the form of an adhesive matrix patch because of a low oral bioavailability, due to an extensive first-pass effect. The patch releases the drug continuously, providing stable plasma levels over 24h and thus continuous dopaminergic stimulation. Independently of patch size, approximately 45% of the rotigotine from the patch is released within 24h (0.2mg/cm2). When single doses of 40cm2 systems are applied to the trunk, there is an average lag time of approximately 3h until the drug is detected in plasma (range 1–8h): Tmin occurs most commonly between 0 and 7h postdose; Tmax typically occurs between 15 and 18h postdose but can occur from 4–27h postdose. After removal of the patch, plasma levels decrease with a terminal half life of 5–7h. Rotigotine displays dose-proportionality over a daily dose range of 2–8mg/24h. In the clinical studies of rotigotine effectiveness, the transdermal system application site was rotated from day to day (abdomen, thigh, hip, flank, shoulder or upper arm) and the mean measured plasma concentrations of rotigotine were stable over the 6 months of maintenance treatment. In healthy subjects, steady-state plasma concentrations of rotigotine were achieved within 2–3 days of daily dosing. Relative bioavailability for the different application sites at steady state was evaluated in subjects with Parkinson’s disease. Differences in bioavailability ranged from less than 1% (abdomen versus hip) to 64% (shoulder versus thigh) with shoulder application showing higher bioavailability. Because rotigotine is administered transdermally, food does not affect absorption of the product, so it can be administered without regard to the timing of meals. The weight normalized apparent volume of distribution (Vd/F) in humans is approximately 84l/kg after repeated dose administration. The binding of rotigotine to human plasma proteins is approximately 92% in vitro and 89.5% in vivo. Rotigotine is extensively metabolized by conjugation and N-dealkylation. Rotigotine is primarily excreted in the urine (~71%) as inactive conjugates of the parent compound and N-desalkyl metabolites. A small amount of unconjugated rotigotine is eliminated renally (<1% of the absorbed dose) [Cawello et al. 2009].
Patches are applied once daily and should be replaced every 24h with the new patch applied to a different site. Patch sizes used in clinical trials in patients with idiopathic RLS were 2.5cm2 (rotigotine released dosage 0.5mg/24h; total drug content in the patch 1.125mg), 5cm2 (1mg/24h; 2.25mg), 10cm2 (2mg/24h; 4.5mg), 15cm2 (3mg/24h; 6.75mg) and 20cm2 (4mg/24h; 9.0mg). The first rotigotine dose for primary RLS is 0.5mg/24h (patch size 2.5cm2), which can be increased in weekly steps of 2mg, if necessary. The maximum dose that can be reached when treating RLS is 4mg/24h (patch size 20cm2). Higher dosages (up to 16mg/24h) are utilized in patients with early or advanced Parkinson’s disease. Withdrawal of rotigotine treatment should be done gradually; the daily dose must be reduced by 2mg every other day, until complete withdrawal is achieved. An abrupt withdrawal of the drug might lead to a syndrome resembling neuroleptic malignant syndrome or akinetic crises [Cawello et al. 2009].
Studies have shown that plasma concentrations of rotigotine in patients 65–80 years of age are similar to those in younger patients (40–64 years of age). Patients affected by moderate impaired hepatic function do not need dose adjustments [Cawello et al. 2007]. It has been demonstrated that the pharmacokinetics of rotigotine in these subjects does not change, whereas the consequence of severe hepatic dysfunction on rotigotine’s pharmacokinetics have not yet been studied. Thus, it is advisable to use rotigotine with caution when hepatic function is severely impaired [Elshoff et al. 2009]. Plasma concentrations of rotigotine do not decrease in patients with renal failure undergoing haemodialysis and the drug has not been observed in the dialysis fluid. In subjects with severe renal impairment not on dialysis (i.e. creatinine clearance 15 to <30ml/min), exposure to rotigotine conjugates is doubled.
The pharmacokinetics of rotigotine in subjects below the age of 18 years have not been established.
Regarding pregnant women, animal studies have not indicated any teratogenic effects in rats and rabbits, but embryo toxicity was observed in rats and mice at maternotoxic doses. Thus, rotigotine should not be used during pregnancy. An effect on lactation has also been demonstrated. Rotigotine indeed decreases prolactin secretion in humans and could potentially inhibit lactation. Studies in rats have shown that rotigotine and/or its metabolite(s) is excreted in breast milk. Although this has not yet been reported in humans, breastfeeding should be discontinued in the absence of human data [Cawello et al. 2005; Jenner, 2005].
The efficacy of rotigotine in treating RLS was first demonstrated by a study conducted by Stiasny-Kolster and colleagues in 2004 [Stiasny-Kolster et al. 2004b]. It was a randomized, double-blind, placebo-controlled, multicentre trial that recruited 63 patients affected by moderate-to-severe idiopathic RLS (mean IRLS score 25.9±5.1) and who had previously responded to L-dopa. Three fixed doses of rotigotine (1.125, 2.25 and 4.5mg) were compared with placebo over a period of 1week. No dose titration was performed. The primary efficacy measure was the total score on the IRLS, while the RLS-6 and the CGI scales were secondary endpoints. RLS severity improved by 10.5 (1.125mg/die, p=0.41), 12.3 (2.25mg/die, p=0.18) and 15.7 points (4.5mg/die, p<0.01) in the IRLS, whereas the improvement with placebo was of only 8 points, thus demonstrating a dose–response relationship. The improvement reached statistical significance only for the 4.5mg/die patch. Regarding the RLS-6 scales, only the 4.5mg/die treatment group demonstrated a significant improvement (p<0.01) in all four severity scales (severity at bedtime, during the night, during the day when at rest, during the day when active). The two lower dosages showed a favourable improvement over placebo in the two scales that assess severity of symptoms during the day, whereas results did not differ from placebo with respect to severity of symptoms at bedtime or during the night. Instead no differences were detected in the RLS-6 scales quality of sleep and tiredness at daytime. Adverse events were rare and mild. Application site reaction represented the most common adverse event, seen in 26.5% of patients treated with rotigotine and in 28.6% of patients treated with placebo. Headache was the second most common side effect (22.4% of patients receiving rotigotine versus 7.1% of patients receiving placebo). Overall adverse events were more frequent in the two higher rotigotine dose groups (2.25 and 4.5mg).
In 2008, Oertel and colleagues conducted a randomized, multicentre, double-blind, placebo-controlled 6-week trial using higher doses of rotigotine [Oertel et al. 2008a]. The study population consisted of severely affected patients with a long history of RLS who had been previously treated with dopaminergic drugs. Subjects received rotigotine patches with fixed doses of 0.5mg/24h (1.125mg), 1mg/24h (2.25mg), 2mg/24h (4.5mg), 3mg/24h (6.75mg), or 4mg/24h (9.0mg). Patients were randomly assigned to one of the six treatment groups and no drug dosage variations were allowed. The primary efficacy variable was the change in IRLS total score from baseline to the end of treatment. A monotone dose–response relationship was observed in the dose range 0.5mg/24h and 3mg/24h. The 0.5mg/24h dose was not statistically significantly superior to placebo. The higher dosage (4mg/24h) showed a minor improvement in the IRLS total score over the 3mg/die dosage. Instead no differences were seen between the effects of 1mg/24h and 2mg/24h. Secondary outcome variables were the CGI, the RLS-6 scales and the QoL. Improvements in the CGI showed a similar dose–response relationship as seen with the IRLS. An improvement of RLS symptoms at bedtime and during the night and a reduced tiredness during the day was demonstrated with the RLS-6 scale. The QoL improved in all treatment groups. Altogether, in this trial, RLS symptoms were improved by rotigotine dosage between 1mg/24h and 3mg/24. Higher doses (4mg/24h) have not demonstrated an additional benefit and were associated with more adverse events. Adverse events were seen in 62% of patients receiving rotigotine and in 45.5% of patients in the placebo group. Application site reaction was the most common side effect seen in 17.5% of patients taking rotigotine and in 1.8% of patients receiving placebo. Serious adverse events were reported by six patients.
Of the 310 patients who completed this trial, 295 patients with a mean IRLS score of 27.8±5.9 were included in an open-label trial that observed safety and tolerability of rotigotine over a period of 1 year. Two groups of patients were distinguished: those whose IRLS showed an improvement of at least 50% stopped treatment with rotigotine but were allowed to restart treatment by entering the trial if the clinical condition worsened during a treatment-free period of 1 week; patients who instead had shown minor improvements in the previous trial entered the second trial immediately. Those patients who had reported severe adverse events or had not been compliant during the double-blind study were excluded. Drug titration started with 0.5mg/24h; the dose could be increased up to a maximum dose of 4mg/24h. The mean daily dose after 12 months was 2.8±1.2mg/24h. Dose adjustments occurred mainly in the first month of therapy, but afterwards doses remained stable. Outcome parameters were: the IRLS sum score, the RLS-6 scale, the CGI and the QoL-RLS. An improvement in all of these efficacy parameters was observed after 12 months. A mean change in the IRLS total score of 17.4 was observed (p<0.001). An improvement of at least 50% in the IRLS total score was seen in 68% patients. Also the RLS-6 severity scale demonstrated an improvement of symptoms at bedtime, during the night, during daytime when patients were at rest and a reduced tiredness during the day (p<0.001). As a consequence, the QoL was improved. Rotigotine was well tolerated; only minor adverse events were observed. Application site reactions occurred in 40% of patients. Nausea and fatigue were the second most common side effects, seen in 9.5% and 6.4% of patients, respectively. Augmentation was not reported [Oertel et al. 2008b].
In 2008 Trenkwalder and colleagues studied the effects of rotigotine over a period of 6 months [Trenkwalder et al. 2008]. Patients affected by idiopathic severe or very severe RLS (mean IRLS sum score 28.1±6.1) were recruited into the study. The majority of the study population had been previously treated with dopaminergic drugs (71.1%). Patients were randomly assigned to receive placebo or rotigotine 1mg/24h, 2mg/24h, and 3mg/24h. Efficacy outcomes were the IRLS sum score, the CGI item 1 and 2, the RLS-6 scales, the QoL-RLS and the Medical Outcomes Study (MOS) sleep scale. A significant improvement in the IRLS sum score and in the CGI was observed for all rotigotine dosages, if compared with placebo at the end of the trial. A dose–response relationship was observed, with the higher effects seen for the rotigotine 3mg/24h. The QoL also improved with a dose–response relationship. Adverse events were reported by 77.7% of patients receiving rotigotine and by 55% of patients receiving placebo. The most common adverse effect was application site drug reaction (42.5% of patients receiving rotigotine).
In addition to published data, we have found information regarding nine unpublished trials. A few of them are reviewed for their interest.
Recently a randomized, double-blind, placebo-controlled trial has assessed the efficacy, safety and tolerability of ascending doses of rotigotine nasal spray for the acute treatment of RLS [ClinicalTrials.gov, 2010a]. An extension of Oertel and colleagues’ trial [ClinicalTrials.gov, 2010b] has recently been completed. This trial (SP 710) was designed to evaluate long-term safety, efficacy correlates, and QoL data in subjects with idiopathic RLS. The duration of the trial was 5 years. Final data collection date for primary outcome measure was April 2009.
Severe RLS can impair the QoL of patients, thus requiring pharmacological treatment. When a secondary form of RLS is recognized, a prompt therapy of the underlying condition must be started in order to look for remission of RLS symptoms. Dopaminergic agents (nonergot dopamine agonists and L-dopa) are considered to be first-line therapies for idiopathic RLS. These drugs are usually preferred when patients do not present with daytime symptoms. However, if daytime symptoms are present, the short half life of these drugs may force the patients to take the medication many times during the day, reducing their compliance. The transdermal continuous delivery of rotigotine avoids these complications. There is a continuous delivery of the drug over 24h and stable plasma levels are soon reached. All clinical trials have demonstrated efficacy and safety of this drug when used in patients affected by moderate-to-severe RLS, both in the short and long term. The longest period that has been evaluated was 1 year, but soon results from a 5-year follow up will be available. RLS symptoms are generally improved by rotigotine in a therapeutic window between 1mg/24h and 3mg/24h. Higher doses (4mg/24h) have not been demonstrated to have an additional benefit and are complicated by more important side effects. The most common adverse events in clinical trials were application site reactions, headache and nausea. They were usually mild and patients did not need to stop their treatment. Augmentation was not reported in these trials, and the less frequent occurrence of augmentation with this compound might help in better understanding its pathophysiology. The continuous delivery of rotigotine can avoid or reduce dopamine overstimulation in the spinal cord or such an application might exert other influences on dopamine homeostasis. Therefore, patches might become an important treatment option for augmented RLS patients. In addition, these patients may benefit from the continuous delivery of the drug, since it reduces also the daytime symptoms which are characteristics of augmentation [Oertel et al. 2008b].
The authors declare that there is no conflict of interest.