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Treatment of restless legs syndrome
Parkinsonism and Related Disorders 15S (2009) S65–S70
Treatment of restless legs syndrome Luigi Ferini-Strambi *, Mauro Manconi Sleep Disorders Center, Department of Neuroscience, Università Vita-Salute San Raffaele, Milan, Italy
A R T I C L E
I N F O
Keywords: Restless legs syndrome Dopamine receptor agonists Augmentation
A B S T R A C T Restless legs syndrome (RLS) is a common condition characterized by an urge to move the legs, accompanied by uncomfortable or unpleasant sensations. Symptoms predominantly occur at rest in the evening or at night, and they are alleviated by moving the affected extremity or by walking. Recent European epidemiological studies reported an overall prevalence of RLS up to 10%, with a female preponderance. The prevalence rates reported in south-eastern Europe are lower, as are those in Asiatic populations. Although the aetiopathogenesis of RLS is still unknown, the rapid and dramatic improvement of RLS with dopaminergic compounds suggests a dopaminergic system dysfunction as the basic mechanism. Extensive data are available for L-dopa and dopamine receptor agonists, especially for pramipexole and ropinirole. Pharmacological treatment should be limited to those patients who suffer from clinically relevant RLS with impaired sleep quality or quality of life. Treatment on demand is a clinical need in RLS cases that present intermittent symptoms. © 2009 Elsevier Ltd. All rights reserved.
1. Introduction Restless legs syndrome (RLS) is a common but frequently underdiagnosed condition, characterized by uncomfortable and unpleasant sensations in the legs, with an urge to move [1]. The symptoms begin or worsen during periods of rest or inactivity: patients describe exacerbation of symptoms in situations such as watching television, driving or flying long distances, and attending business meetings [2]. The urge to move and the unpleasant leg sensations are relieved by activity, and this relief generally persists as long as the activity continues. Another central characteristic of RLS is the worsening of symptoms in the evening or during the night [1]. Some studies have investigated the circadian pattern in the occurrence of RLS symptoms [3]. These studies showed that the severity of leg discomfort followed a circadian rhythm with a maximum occurring after midnight and a minimum occurring at 10:00 in the morning. Some investigators found that changes in melatonin secretion precede the increase in sensory or motor symptoms of RLS [4]. Interestingly, there is an inverse relationship between the circadian curve of melatonin secretion and that of dopamine activity. Even though the underlying pathophysiology of RLS is still not fully understood, the most accredited hypothesis recognizes an involvement of the diencephalic A11 dopaminergic neurons. These dopaminergic cells seem to be able to modulate the nociceptive
* Correspondence to: L. Ferini-Strambi, Sleep Disorders Center, Università VitaSalute San Raffaele, Via Stamira d’ Ancona 20, 20127 Milan, Italy. Tel.: +39 02 26433363; fax: +39 02 26433394. E-mail address: [email protected] (L. Ferini-Strambi). 1353-8020/$ – see front matter © 2009 Elsevier Ltd. All rights reserved.
afferents by means of their projections into the dorsal horns of the spinal cord. Specific lesions in A11 nuclei of rats induced some features similar to those of human RLS with a long latency of sleep, a reduced sleep time, and several episodes of standing upright. In a recent study, locomotor activity was evaluated in four mice groups: normal mice, mice with A11 lesions, mice fed with a low-iron diet, and mice with A11 lesions combined with iron deprivation [5]. Locomotor activity was increased in both the A11-lesioned and iron-deprived mice compared with normal mice. In the group combining A11 lesions with iron deprivation, the mice showed further augmented motor activity [5]. Increased locomotor activity either during the end of the active or during the inactive period, similar to human RLS, has been recently reported in other animal studies characterized by dietary iron deprivation [6]. The role of iron status in RLS pathophysiology has also been evaluated in humans. A reduced brain iron content was observed in RLS patients by autopsies, magnetic resonance and transcranial ultrasound imaging studies, and cerebrospinal fluid analyses [7]. Brain iron deficiency might cause abnormalities in dopaminergic systems and, consequently, induce RLS symptoms [7]. The majority of RLS patients complain of poor sleep. Most patients report difficulty falling asleep since both immobility and circadian factors facilitate the occurrence of RLS symptoms at bedtime. However, some patients fall asleep rapidly but wake up shortly after with unpleasant legs sensations that force them to get up and walk around in order to alleviate the symptoms. Sleep laboratory investigations showed that more than 85% of patients with RLS also experience stereotyped repetitive movements once asleep, a condition known as periodic limb movements (PLM) during sleep (PLMS). PLMS are characterized by rhythmic
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Fig. 1. Polysomnographic sample of bilateral periodic leg movements on the right anterior tibialis (RAT) and the left anterior tibialis (LAT) muscles during NREM sleep. Electroencephalographic channels referred to the controlateral mastoid (C3-A2; CZ-A2; O2-A1); right ocular cantus (ROC); left ocular cantus (LOC).
extensions of the big toe and dorsiflexions of the ankle with occasional flexions of the knee and hip (Fig. 1). According to standard criteria [8], PLMS are scored only if they are part of a series of four or more consecutive movements lasting 0.5 to 5 s with an inter-movement interval of 4 to 90 s. A PLMS index (number of PLMS per hour of sleep) greater than 15 for the entire night of sleep is considered pathological [1]. In addition to PLMS, RLS patients also show PLM during wakefulness, known as PLMW. RLS can occur in all ethnic backgrounds; however, epidemiological studies have shown that Caucasian people are most affected. Most surveys of Caucasian populations show a prevalence of approximately 10%, whereas surveys of south-eastern Europe and Asian populations report much lower prevalences. A rate of 3.2% has been reported in Turkey, 3.9% in central Greece, and 0.6% in Singapore [9]. In an epidemiological survey conducted in the USA and 5 European countries [10], RLS symptoms of any frequency were reported by 7.2% of the general population: symptoms occurred at least 2 times/week and were reported as moderately or severely distressing by 2.7%, and these people were defined as RLS sufferers and probably represented those that should be adequately treated. RLS may be classified in primary or secondary forms. In the primary forms, there is substantial evidence for a genetic contribution to RLS [3]. Familial aggregation has been well documented, with about 50% of idiopathic cases reporting a positive family history of RLS: in most families, it segregates in an autosomal dominant fashion, with a high penetrance rate (90–100%) [9]. Linkage studies in RLS families have revealed eight loci but no causally related sequence variant has been identified using this approach [9]. A recent genome-wide association study of RLS identified common variants in three genomic regions: MEIS1, BTBD9 and MAP2K5 on chromosomes 2p, 6p and 15q, respectively. Each genetic variant was associated with more than a 50% increase in risk of RLS [11]. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder. A genome-wide significant association with a common variant in an intron of BTBD9 on chromosome 6p was found independently in the Icelandic population [12]. An association between this variant and PLMS without RLS (and the absence of
such an association for RLS without PLMS) suggests that it is a genetic determinant of PLMS. The most common causes of secondary RLS are iron deficiency, end-stage renal disease and pregnancy [1–3]. Peripheral neuropathies of different origin, diabetes mellitus and multiple sclerosis have been seen at higher than expected rates in RLS patients [13–15]. Moreover, RLS as a side-effect is ascribed to several drugs, and the majority of published papers focusing on this issue are case reports. An epidemiological study on the prevalence of RLS showed that the intake of selective serotonin re-uptake inhibitors is associated with an increased risk of RLS (odds ratio = 3 : 1). A recent prospective study addressed this problem for the class of second-generation antidepressants (ADs) [16]. Patients treated for the first time with an AD were prospectively evaluated with regard to the question of whether RLS occurred or pre-existing RLS worsened as a result of the AD. In 9% of patients, RLS was observed as a side-effect related to the AD treatment. This finding was most pronounced with mirtazapine, provoking or deteriorating RLS in 28% of patients. Of the patients who had no RLS before the start of treatment, 8% developed RLS during AD treatment and this side-effect occurred after a median of 2.5 days. Of the patients with pre-existing RLS, 13% experienced marked RLS deterioration. According to some authors [17], an important determinant of the clinical tolerability of ADs in RLS seems to be whether the patient has already been treated for RLS or not. If a patient has sufficiently been treated for RLS, he/she usually tolerates ADs. With regard to treatment for RLS, the development of validated rating scales and standardized diagnostic criteria have vastly improved the quality of RLS treatment trials. Several medications have shown outstanding efficacy; however, all of them provide only symptomatic relief rather than a real “curative” effect. Dopaminergic agents are considered first-line treatment for RLS [3,17]. Non-pharmacological treatments have rarely been investigated. 2. Non-pharmacological treatment There are only very few and not well-controlled studies on non-pharmacological treatments for RLS. A recent 12-week ran-
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domized controlled trial evaluated the effectiveness of an exercise programme on RLS [18]. Study participants were randomized to either exercise (a conditioning programme of aerobic and lower-body resistance training 3 days per week) or control groups. At the end of the 12 weeks, a significant improvement in RLS symptoms was observed in the exercise group compared with controls. In the management of RLS, it is important to inform the patient to maintain good sleep hygiene to prevent the development of insomnia, which is frequently observed. Indeed, some patients go to bed later at night and remain active during hours when their symptoms make sleep difficult, and some severe RLS patients may even change their working schedule for that purpose. Moreover, patients should avoid alcohol, caffeine and heavy meals in the evening since these may aggravate RLS symptoms. Improvement of RLS symptoms has been anecdotally reported with hot baths or application of something hot or cold, or performing tasks requiring a large amount of concentration and so keeping the patient’s mind alert [3]. Recently, a proof-of-concept study on cognitive behavioural therapy tailored to RLS showed favourable results in both medicated and unmedicated RLS patients [19]. Both groups took part in eight group sessions on a weekly basis (session of 90 min each). Subjective ratings of RLS severity, as well as quality of life and mental health status of the patients, had improved at the end of therapy and at follow-up 3 months later. These results suggest that psychological strategies may be included in an integrated treatment approach in RLS.
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from 85% after 2 years to 31% after a mean of 31 months [9,17]. The most frequent adverse effects of L -dopa reported in a large controlled trial were nausea (10.4%), headache (9.3%), fatigue (4.4%), and nasopharyngitis (4.4%). However, the most relevant clinical side-effect of L -dopa therapy is augmentation. Augmentation [9] is a phenomenon characterized by an earlier onset of symptoms by at least 4 hours or by an earlier onset between 2 and 4 hours plus at least one of the following compared with symptom status before treatment: (a) shorter latency to symptoms when at rest; (b) extension of symptoms to other body parts; (c) greater intensity of symptoms; or (d) shorter duration of relief from treatment. Augmentation is probably triggered by intense dopaminergic stimulation of the D1 receptor compared with the D2 and D3 receptors, predominantly at the spinal level. Iron deficiency and sleep deprivation may increase the risk of augmentation [9]. Prevalence rates of augmentation in open-label trials with L dopa range from 18.6% to 72% [22]. Recently, a study that employed a specific scale for measuring the phenomenon (Augmentation Severity Rating Scale, ASRS) showed augmentation in 36 of 60 (60%) patients treated for 6 months with L -dopa (median daily dose 300 mg; range, 50–500 mg) [23]. Increased severity of RLS and higher dosage of L -dopa are associated with higher risk of developing augmentation: maximum dosages of 300–400 mg should not be exceeded [17]. Mild augmentation could be treated by lower dosages divided for afternoon, evening, and at night, but in severe cases the medication should be discontinued. 3.2. Dopamine receptor agonists
3. Pharmacological treatment of idiopathic RLS The high prevalence of RLS does not necessarily mean that all patients should be treated with pharmacological therapy. Pharmacological treatment should be limited to those patients who suffer from clinically relevant RLS symptoms, including intermittent RLS with impaired sleep quality or quality of life [9,17]. All recent trials have focused the primary outcome measure on the International RLS Severity Scale (IRLS; a 10-item scale, each item with a score of 0 to 4: a total of 1 to 10 indicates mild; 11 to 20 moderate; 21 to 30 severe; and 31 to 40 very severe RLS) or polysomnographic sleep parameters (especially PLM index). According to evidence-based medicine criteria, dopaminergic medications should be the first-line therapy in RLS [20]. 3.1. L -dopa Several open-label studies documented the short-term efficacy of L -dopa given with a dopa-decarboxylase inhibitor [3]. Doses between 100 and 200 mg standard L -dopa improve RLS symptoms as measured on a visual analogue scale [9,17]. L -dopa is a shortacting medication and the immediate response without a long titration period is really appreciated by the patient. A positive response to this drug with the first dosage strongly supports the diagnosis of RLS [21]. However, a possible side-effect of L -dopa is morning rebound, characterized by the presence of RLS symptoms occurring de novo as a consequence of evening or night-time treatment. With L -dopa, it is also possible to observe a rebound of PLMS in the last part of the night when L -dopa is administered only at bedtime [3]. In rebound, the reappearance of symptoms is compatible with the timing of withdrawal from medication: indeed, the plasma half-life of L -dopa is very short (1–2 hours) and the beneficial effect rapidly decreases. If RLS persists in the second half of the night, an additional dose of slow-release L -dopa (100 mg) may be given in combination with standard L -dopa 1 hour prior to or at bedtime [17]. Some studies examined the long-term benefit of L -dopa and found various rates of persistent efficacy ranging
Several double-blind controlled studies have shown that both ergoline (cabergoline, pergolide) and non-ergoline (ropinirole, pramipexole, and rotigotine) dopamine receptor agonists are able to control RLS symptomatology (Table 1). There are insufficient data for other compounds, such as lisuride and bromocriptine. In short-term follow-up studies, the D2 receptor agonist bromocriptine was found effective in treating RLS and PLMS [9,17]. However, bromocriptine is frequently associated with severe adverse effects, especially nausea, responsible for withdrawal from bromocriptine shortly after the onset of treatment. Pergolide, another D2 receptor agonist was more extensively studied and its efficacy has been well-documented in short- and long-term follow-up studies [9,17]. Pergolide was also found superior to L -dopa in alleviating symptoms of RLS. In 28 patients treated for 416 days with pergolide, persistent efficacy was noted in 79% of patients but adverse effects were noted in 71%, including augmentation in 27% of cases [9,17]. Cabergoline, a long-acting D2 receptor agonist, was also used successfully to treat RLS [17,20]. An open long-term study showed that the beneficial effects of low-dose cabergoline (mean dosage = 2.2 mg) on RLS symptoms persist throughout a follow-up period up to 1 year [24]. The most common side-effects observed in open and double-blind studies are nausea, constipation, headache, and orthostatic hypotension [17]. No augmentation has been reported
Table 1 Dopamine agonists in RLS
Lisuride Bromocriptine Cabergoline Pergolide Pramipexole Ropinirole Rotigotine
Half-life (hours)
Initial dosage (mg)
Usual dosage range (mg)
2–3 3–8 65 7–16 8–12 6 Constant plasma levels (patch)
0.1 1.25 0.5 0.05 0.125 0.25 0.5 or 1
0.1–2 2.5–5 0.5–2 0.1–0.75 0.125–0.5 0.5–4 0.5–3
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in a single-blind 1-year study in a small number of RLS patients treated with cabergoline [25]. A more recent controlled study using the ASRS showed a rate of augmentation of 4% [20]. Retroperitoneal, pericardial and pleuropulmonary fibrosis are well known but rare complications of the treatment with ergoline dopamine receptor agonists. Recently, two studies showed that pergolide and cabergoline have a similar risk of inducing valvular heart disease and cardiac-valve regurgitation [26,27]. This possible side-effect has not been reported in controlled RLS trials. However, there are two case reports regarding the occurrence of pleuropulmonary fibrosis and valvular heart disease after pergolide treatment in RLS patients [28,29]. In recent years, two non-ergoline derivatives, pramipexole and ropinirole, have been extensively studied for RLS treatment. Montplaisir et al. [30] evaluated pramipexole, a full agonist with high affinity for the D3 receptor subtype, in a crossover placebocontrolled study. They found that the compound was very effective in treating RLS and in suppressing PLMS. Another recent double-blind placebo-controlled study [31] confirmed the efficacy of pramipexole (median dose 0.35 mg/day). Some recent long-term follow-up studies of patients treated with pramipexole [9,17,20] showed a sustained efficacy of the drug in more than 80% of RLS patients. Augmentation with pramipexole was reported in open trials in 8.5–39% of patients [17]. Some randomized placebo-controlled trials have shown that ropinirole is also effective in treating RLS [20]. In a flexible dosetitration polysomnographic trial, a mean dose of 1.8 mg ropinirole significantly reduced PLM and improved sleep parameters [32]. A long-term open-label study showed that ropinirole (mean dose 1.90 mg/day) maintained its therapeutic efficacy in 82% of RLS patients [33]. There were no reports of augmentation in the published studies, but the phenomenon was not systematically assessed. In the absence of comparative trials of pramipexole versus ropinirole, a recent meta-analysis compared the efficacy and tolerability of these two dopamine receptor agonists [34]. The direct meta-analysis confirmed superior efficacy for both treatments versus placebo in reducing RLS. Placebo comparisons showed a significantly higher incidence of nausea with pramipexole, whereas nausea, vomiting, dizziness and somnolence were significantly higher with ropinirole. The indirect comparison showed, with a probability of >95%, a superior reduction in mean IRLS score and significantly lower incidence of nausea, vomiting, and dizziness for pramipexole compared with ropinirole [34]. A first-night effect of pramipexole [35] and ropinirole [36] has been observed in RLS patients. A low dose of both drugs induces a significant effect on symptoms subjectively reported, as well as a significant improvement in PLMS. Sleepiness associated with sudden onset of sleep has been reported in patients with Parkinson’s disease (PD) treated with pramipexole and ropinirole. In RLS patients, sleepiness might be seen during treatment with dopamine receptor agonists but is much less problematic [3]; moreover, these compounds in RLS may, in contrast to PD, reduce the risk of sudden onset of sleep, probably due to their beneficial effect on sleep [37]. It has been suggested that striatal and limbic dysregulation in PD are putative factors in compulsive behaviours arising from dopamine receptor agonists. Recently, behavioural complications, such as pathological gambling and punding, have also been reported in some RLS patients undergoing dopaminergic treatment [38–41]. Rotigotine is a new non-ergoline agonist of D3, D2 and D1 dopamine receptors, with an almost 15-fold higher affinity for the D2 receptor than for the D1 receptor. In three placebocontrolled trials, transdermal rotigotine demonstrated significant improvement in RLS severity [42,41–44]. Transdermal 24-hour delivery of low-dose rotigotine (patch with 1–3 mg) may relieve
the night-time and daytime symptoms of RLS: the beneficial effects persist up to 6 months. To date, no signs of augmentation have been reported in the trials with rotigotine. Low rates of typical dopaminergic side-effects have been observed in patients who receive rotigotine. However, skin reactions, mostly mild or moderate, are often seen at the application site of the patch; the rate increases with increasing rotigotine dose and can be minimized by changing the application site daily [42–44]. 3.3. Non-dopaminergic treatments Several open-label and controlled clinical trials have evaluated the therapeutic effect of opioids in RLS and these compounds have long been known to successfully treat RLS [17]. Oxycodone administered at a mean daily dose of 11.4 mg both improved subjective ratings and decreased PLMS in 11 RLS patients, with evidence for decreased arousals and improved sleep efficiency [17,20]. A persistent effect of opioids was more recently reported in long-term follow-up studies [17,20]. Opioids may be prescribed in severe cases, especially to those unresponsive to other treatments. Although there is little evidence of tolerance or addiction to opioids in the RLS literature, the prescription of these compounds should be restricted to patients without a previous history of substance abuse. Interestingly, it has been reported that tramadol may cause augmentation [45]. Gabapentin is an anti-epileptic with multiple mechanisms of action, including inhibition of the alpha (delta) subunit of the sodium channel. A subjective improvement of RLS with gabapentin at doses of 300 to 2,400 mg a day has been reported in some openlabel trials and one placebo-controlled study [17,20]. Gabapentin produces few adverse effects except for mild daytime somnolence. An open clinical trial [46] compared the efficacy of gabapentin and ropinirole in patients with idiopathic RLS. This study showed that both compounds provided a similarly well-tolerated and effective treatment for RLS and PLMS. In patients who have developed adverse effects with dopaminergic medications, gabapentin may be a valuable alternative [17]. Other anticonvulsants, such as carbamazepine and valproic acid, have been evaluated in RLS but seem to be less effective than gabapentin [17]. Despite their past widespread use, there is little data to support the use of benzodiazepines for RLS. Several studies showed that clonazepam, nitrazepam, lorazepam and temazepam improve the quality of sleep, reduce PLMS and /or PLMS associated with arousals in patients with RLS. However, the therapeutic effects of benzodiazepines on subjective ratings of RLS symptoms were either modest or non-significant [3]. Therefore benzodiazepines are mostly used to improve sleep continuity in patients with RLS. A recent paper [47] evaluated the effect of hydrocortisone infusion on RLS symptoms. A pathophysiological relationship between corticosteroid secretion and RLS could be hypothesized since plasma cortisol levels display a morning peak, afternoon decline, and nadir around midnight: an inverse temporal course is exactly observed for RLS symptoms. In a 1-week double-blind placebo-controlled study, Hornyak and co-workers [47] found an improvement in symptoms in 5 of the 10 patients treated by a single dose of intravenous hydrocortisone 40 mg in the evening. On the other hand, in RLS the improvement of symptoms with physical activity may be associated with the known changes in hypothalamic-pituitary-adrenal axis activity of cortisol levels that increase during physical exercise. Moreover, cortisol has been described as enhancing the secretion of dopamine in the central nervous system.
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3.4. Treatment of secondary RLS In RLS patients with iron deficiency, iron supplementation has been shown to improve RLS [17]. When a patient’s ferritin level is <45–50 μg/L, oral iron treatment is indicated as supplemental treatment. Oral iron treatment can be ferrous sulphate 325 mg, or its equivalent, with vitamin C 100–200 mg, taken twice a day, preferably on an empty stomach if the iron is tolerated. Since iron is not absorbed very well in the gastrointestinal tract, treatment with intravenous iron infusion could be more effective, but anaphylaxis is a possible adverse event after administration of intravenous iron. A recent randomized, double-blind, placebo-controlled trial of intravenous iron sucrose (1,000 mg/day) failed to demonstrate the significant improvement in RLS reported in prior open-label studies [48]. However, patients with normal ferritin levels were also included in that study. Another randomized double-blind placebo-controlled trial with intravenous iron sucrose (1,000 mg/day) evaluated RLS patients with serum ferritin <45 μg/L [49]. This study showed a lack of superiority of iron sucrose compared with saline at 11 weeks, but found evidence that iron sucrose reduced RLS symptoms both in the acute phase (7 weeks) and during long-term follow-up (12 months). The RLS seen in patients on dialysis is often severe. Compared with idiopathic RLS, series show similar or increased overall severity, increased PLMS, increased wakeful leg movements, and a more rapid progression [50]. Dialysis does not improve RLS. In RLS patients with renal insufficiency, successful kidney transplant may lead to complete remission of RLS within days or weeks [51]. Complete remission of symptomatology is also usually observed after delivery in patients with pregnancy-related RLS [52]. Some investigators have suggested that gabapentin [20] or pregabalin [53] may be preferentially effective in the treatment of secondary RLS for patients with neuropathy. It is well known that these compounds improve neuropathic pain. A combination of sedative and sensory modulating actions of gabapentin and pregabalin might explain their effect in RLS. However, these compounds should be further investigated in randomized placebocontrolled trials. 4. Conclusion As with many chronic disorders, RLS varies considerably in both symptom severity and degree of impact on health and wellbeing. Preliminary studies of non-pharmacological approaches to RLS treatment have shown positive results and encourage further trials. In patients with mild RLS, good sleep hygiene should be recommended. Patients should be advised to avoid alcohol, caffeine and heavy meals before going to sleep. Bedtime hours should be regular and activity should be gradually reduced in the evening. Pharmacological treatment should be limited to those patients who suffer from clinically relevant RLS symptoms. Treatment on demand is a clinical need in certain RLS patients, but unfortunately intermittent therapy for RLS has not been investigated in clinical trials. Some pharmacological data and clinical experience suggest that L -dopa 100 mg or pramipexole 0.25 mg may be used for intermittent therapy during daytime or at sleep onset. Most patients with idiopathic RLS respond robustly to dopaminergic agents. The best strategy is to start pharmacological therapy cautiously and at the lowest recommended doses. L -dopa improves RLS, but is associated with a high incidence of symptom rebound and augmentation. Rebound with L -dopa is related to its short half-life. Augmentation, mainly characterized by the occurrence of RLS symptoms earlier in the day, is a phenomenon less frequently observed with dopamine receptor agonists. Since ergot-derived
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compounds can cause pleural, pericardial, and retroperitoneal fibrosis, non-ergot dopamine receptor agonists are preferred. Due to their tolerability and half-life, the D3 receptor agonists pramipexole and ropinirole have become the first-line treatment in RLS. Recent papers have shown the efficacy of transdermal rotigotine in the treatment of RLS: stable drug concentrations over 24 hours seem to be a favourable strategy to also cover daytime symptoms and probably avoid augmentation. Other treatment (second-line) options for RLS include gabapentin and opioids. Gabapentin may be used if dopamine receptor agonists are not tolerated or fail. Opioids are a highly effective therapy in advanced and severe forms of RLS. High-dose intravenous iron could be promising, but is still an experimental approach. In recent years, some studies have shown that there is a significant association between certain health factors and RLS. In severe RLS, a significant relationship with health problems such as cardiovascular diseases and hypertension has been found [54–56]. Sleep loss and the presence of PLMS might explain the increased cardiovascular risk in RLS patients, and this increased risk may justify the pharmacological treatment of moderate/severe RLS cases. Conflict of interest Luigi Ferini-Strambi has received honoraria for serving on scientific advisory boards for Boehringer-Ingelheim, UCB-Schwarz Pharma, GlaxoSmithKline, Sanofi-Aventis, and Transcept Pharmaceuticals. Mauro Manconi has no potential conflict of interest to declare. References [1] American Academy of Sleep Medicine. International Classification of Sleep Disorders. Diagnostic and Coding Manual. Westchester, IL: American Academy of Sleep Medicine; 2005. [2] Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institute of Health. Sleep Med 2003; 4:101–19. [3] Montplaisir J, Allen R, Walters A, Ferini-Strambi L. Restless legs syndrome and periodic limb movements during sleep. In: Kryger MH, Roth T, Dement WC, editors. Principles and Practice of Sleep Medicine. 4th ed.. Philadelphia: Elsevier, 2005. p. 839–52. [4] Michaud M, Dumont M, Selmaoui B, Paquet J, Fantini ML, Montplaisir J. Circadian rhythm of restless legs syndrome symptoms: relationship with biological markers. Ann Neurol 2004;55:372–80. [5] Qu S, Le W, Zhang X, Xie W, Zhang A, Ondo WG. Locomotion is increased in a11-lesioned mice with iron deprivation: a possible animal model for restless legs syndrome. J Neuropathol Exp Neurol 2007;66:383–8. [6] Dean T Jr, Allen RP, O’Donnell CP, Earley CJ. The effects of dietary iron deprivation on murine circadian sleep architecture. Sleep Med 2006;7:634– 40. [7] Allen RP, Earley CJ. The role of iron in restless legs syndrome. Mov Disord 2007;22 Suppl 18:S440–8. [8] Coleman RM. Periodic movements in sleep (nocturnal myoclonus) and restless legs syndrome. In: Guilleminault C, editor. Sleeping and waking disorders: indications and techniques. Menlo Park, CA: Addison-Wesley; 1982. p. 265– 95. [9] Trenkwalder C, Högl B, Winkelmann J. Recent advances in the diagnosis, genetics and treatment of restless legs syndrome. J Neurol 2009;256:539–53 [10] Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005;165:1286–92. [11] Winkelmann J, Schormair B, Lichtner P, Ripke S, Xiong L, Jalilzadeh S, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet 2007;39:1000–6. [12] Stefansson H, Rye DB, Hicks A, Petursson H, Ingason A, Thorgeirsson TE, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2007;357:639–47. [13] Gemignani F, Brindani F. Restless legs syndrome associated with peripheral neuropathy. Eur J Neurol 2007;14:e9–e10.
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[36] Saletu B, Gruber G, Saletu M, Brandstätter N, Hauer C, Prause W, et al. Sleep laboratory studies in restless legs syndrome patients as compared with normals and acute effects of ropinirole. 1. Findings on objective and subjective sleep and awakening quality. Neuropsychobiology 2000;41:181–9. [37] Möller C, Körner Y, Cassel W, Meindorfner C, Krüger HP, Oertel WH, et al. Sudden onset of sleep and dopaminergic therapy in patients with restless legs syndrome. Sleep Med 2006;7:333–9. [38] Evans AH, Butzkueven H. Dopamine agonist-induced pathological gambling in restless legs syndrome due to multiple sclerosis. Mov Disord 2007;22:590–1. [39] Quickfall J, Suchowersky O. Pathological gambling associated with dopamine agonist use in restless legs syndrome. Parkinsonism Relat Disord 2007;13:535–6. [40] Tippmann-Peikert M, Park JG, Boeve BF, Shepard JW, Silber MH. Pathologic gambling in patients with restless legs syndrome treated with dopaminergic agonists. Neurology 2007;68:301–3. [41] Evans AH, Stegeman JR. Punding in patients on dopamine agonists for restless leg syndrome. Mov Disord 2009;24:140–1. [42] Stiasny-Kolster K, Kohnen R, Schollmayer E, Möller JC, Oertel WH; Rotigotine Sp 666 Study Group. Patch application of the dopamine agonist rotigotine to patients with moderate to advanced stages of restless legs syndrome: a double-blind, placebo-controlled pilot study. Mov Disord 2004;19:1432–8. [43] Oertel WH, Benes H, Garcia-Borreguero D, Geisler P, Högl B, Saletu B, et al. Efficacy of rotigotine transdermal system in severe restless legs syndrome: a randomized, double-blind, placebo-controlled, six-week dose-finding trial in Europe. Sleep Med 2008;9:228–39. [44] Trenkwalder C, Benes H, Poewe W, Oertel WH, Garcia-Borreguero D, de Weerd AW, et al. Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2008;7:595–604. [45] Earley CJ, Allen RP. Restless legs syndrome augmentation associated with tramadol. Sleep Med 2006;7:592–3. [46] Happe S, Sauter C, Klösch G, Saletu B, Zeitlhofer J. Gabapentin versus ropinirole in the treatment of idiopathic restless legs syndrome. Neuropsychobiology 2003;48:82–6. [47] Hornyak M, Rupp A, Riemann D, Feige B, Berger M, Voderholzer U. Low-dose hydrocortisone in the evening modulates symptom severity in restless legs syndrome. Neurology 2008;70:1620–2. [48] Earley CJ, Horská A, Mohamed MA, Barker PB, Beard JL, Allen RP. A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome. Sleep Med 2009;10:206–11. [49] Grote L, Leissner L, Hedner J, Ulfberg J. A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Mov Disord 2009;24:1445–52. [50] Enomoto M, Inoue Y, Namba K, Munezawa T, Matsuura M. Clinical characteristics of restless legs syndrome in end-stage renal failure and idiopathic RLS patients. Mov Disord 2008;23:811–6. [51] Molnar MZ, Novak M, Ambrus C, Szeifert L, Kovacs A, Pap J, et al. Restless Legs Syndrome in patients after renal transplantation. Am J Kidney Dis. 2005;45:388–96. [52] Manconi M, Govoni V, De Vito A, Economou NT, Cesnik E, Casetta I, et al. Restless legs syndrome and pregnancy. Neurology 2004;63:1065–9. [53] Sommer M, Bachmann CG, Liebetanz KM, Schindehütte J, Tings T, Paulus W. Pregabalin in restless legs syndrome with and without neuropathic pain. Acta Neurol Scand 2007;115:347–50. [54] Winkelman JW, Finn L, Young T. Prevalence and correlates of restless legs syndrome symptoms in the Wisconsin Sleep Cohort. Sleep Med 2006;7:545– 52. [55] Pennestri MH, Montplaisir J, Colombo R, Lavigne G, Lanfranchi PA. Nocturnal blood pressure changes in patients with restless legs syndrome. Neurology 2007;68:1213–8. [56] Winkelman JW, Shahar E, Sharief I, Gottlieb DJ. Association of restless legs syndrome and cardiovascular disease in the Sleep Heart Health Study. Neurology 2008;70:35–42.
Treatment of restless legs syndrome Luigi Ferini-Strambi *, Mauro Manconi Sleep Disorders Center, Department of Neuroscience, Università Vita-Salute San Raffaele, Milan, Italy
A R T I C L E
I N F O
Keywords: Restless legs syndrome Dopamine receptor agonists Augmentation
A B S T R A C T Restless legs syndrome (RLS) is a common condition characterized by an urge to move the legs, accompanied by uncomfortable or unpleasant sensations. Symptoms predominantly occur at rest in the evening or at night, and they are alleviated by moving the affected extremity or by walking. Recent European epidemiological studies reported an overall prevalence of RLS up to 10%, with a female preponderance. The prevalence rates reported in south-eastern Europe are lower, as are those in Asiatic populations. Although the aetiopathogenesis of RLS is still unknown, the rapid and dramatic improvement of RLS with dopaminergic compounds suggests a dopaminergic system dysfunction as the basic mechanism. Extensive data are available for L-dopa and dopamine receptor agonists, especially for pramipexole and ropinirole. Pharmacological treatment should be limited to those patients who suffer from clinically relevant RLS with impaired sleep quality or quality of life. Treatment on demand is a clinical need in RLS cases that present intermittent symptoms. © 2009 Elsevier Ltd. All rights reserved.
1. Introduction Restless legs syndrome (RLS) is a common but frequently underdiagnosed condition, characterized by uncomfortable and unpleasant sensations in the legs, with an urge to move [1]. The symptoms begin or worsen during periods of rest or inactivity: patients describe exacerbation of symptoms in situations such as watching television, driving or flying long distances, and attending business meetings [2]. The urge to move and the unpleasant leg sensations are relieved by activity, and this relief generally persists as long as the activity continues. Another central characteristic of RLS is the worsening of symptoms in the evening or during the night [1]. Some studies have investigated the circadian pattern in the occurrence of RLS symptoms [3]. These studies showed that the severity of leg discomfort followed a circadian rhythm with a maximum occurring after midnight and a minimum occurring at 10:00 in the morning. Some investigators found that changes in melatonin secretion precede the increase in sensory or motor symptoms of RLS [4]. Interestingly, there is an inverse relationship between the circadian curve of melatonin secretion and that of dopamine activity. Even though the underlying pathophysiology of RLS is still not fully understood, the most accredited hypothesis recognizes an involvement of the diencephalic A11 dopaminergic neurons. These dopaminergic cells seem to be able to modulate the nociceptive
* Correspondence to: L. Ferini-Strambi, Sleep Disorders Center, Università VitaSalute San Raffaele, Via Stamira d’ Ancona 20, 20127 Milan, Italy. Tel.: +39 02 26433363; fax: +39 02 26433394. E-mail address: [email protected] (L. Ferini-Strambi). 1353-8020/$ – see front matter © 2009 Elsevier Ltd. All rights reserved.
afferents by means of their projections into the dorsal horns of the spinal cord. Specific lesions in A11 nuclei of rats induced some features similar to those of human RLS with a long latency of sleep, a reduced sleep time, and several episodes of standing upright. In a recent study, locomotor activity was evaluated in four mice groups: normal mice, mice with A11 lesions, mice fed with a low-iron diet, and mice with A11 lesions combined with iron deprivation [5]. Locomotor activity was increased in both the A11-lesioned and iron-deprived mice compared with normal mice. In the group combining A11 lesions with iron deprivation, the mice showed further augmented motor activity [5]. Increased locomotor activity either during the end of the active or during the inactive period, similar to human RLS, has been recently reported in other animal studies characterized by dietary iron deprivation [6]. The role of iron status in RLS pathophysiology has also been evaluated in humans. A reduced brain iron content was observed in RLS patients by autopsies, magnetic resonance and transcranial ultrasound imaging studies, and cerebrospinal fluid analyses [7]. Brain iron deficiency might cause abnormalities in dopaminergic systems and, consequently, induce RLS symptoms [7]. The majority of RLS patients complain of poor sleep. Most patients report difficulty falling asleep since both immobility and circadian factors facilitate the occurrence of RLS symptoms at bedtime. However, some patients fall asleep rapidly but wake up shortly after with unpleasant legs sensations that force them to get up and walk around in order to alleviate the symptoms. Sleep laboratory investigations showed that more than 85% of patients with RLS also experience stereotyped repetitive movements once asleep, a condition known as periodic limb movements (PLM) during sleep (PLMS). PLMS are characterized by rhythmic
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Fig. 1. Polysomnographic sample of bilateral periodic leg movements on the right anterior tibialis (RAT) and the left anterior tibialis (LAT) muscles during NREM sleep. Electroencephalographic channels referred to the controlateral mastoid (C3-A2; CZ-A2; O2-A1); right ocular cantus (ROC); left ocular cantus (LOC).
extensions of the big toe and dorsiflexions of the ankle with occasional flexions of the knee and hip (Fig. 1). According to standard criteria [8], PLMS are scored only if they are part of a series of four or more consecutive movements lasting 0.5 to 5 s with an inter-movement interval of 4 to 90 s. A PLMS index (number of PLMS per hour of sleep) greater than 15 for the entire night of sleep is considered pathological [1]. In addition to PLMS, RLS patients also show PLM during wakefulness, known as PLMW. RLS can occur in all ethnic backgrounds; however, epidemiological studies have shown that Caucasian people are most affected. Most surveys of Caucasian populations show a prevalence of approximately 10%, whereas surveys of south-eastern Europe and Asian populations report much lower prevalences. A rate of 3.2% has been reported in Turkey, 3.9% in central Greece, and 0.6% in Singapore [9]. In an epidemiological survey conducted in the USA and 5 European countries [10], RLS symptoms of any frequency were reported by 7.2% of the general population: symptoms occurred at least 2 times/week and were reported as moderately or severely distressing by 2.7%, and these people were defined as RLS sufferers and probably represented those that should be adequately treated. RLS may be classified in primary or secondary forms. In the primary forms, there is substantial evidence for a genetic contribution to RLS [3]. Familial aggregation has been well documented, with about 50% of idiopathic cases reporting a positive family history of RLS: in most families, it segregates in an autosomal dominant fashion, with a high penetrance rate (90–100%) [9]. Linkage studies in RLS families have revealed eight loci but no causally related sequence variant has been identified using this approach [9]. A recent genome-wide association study of RLS identified common variants in three genomic regions: MEIS1, BTBD9 and MAP2K5 on chromosomes 2p, 6p and 15q, respectively. Each genetic variant was associated with more than a 50% increase in risk of RLS [11]. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder. A genome-wide significant association with a common variant in an intron of BTBD9 on chromosome 6p was found independently in the Icelandic population [12]. An association between this variant and PLMS without RLS (and the absence of
such an association for RLS without PLMS) suggests that it is a genetic determinant of PLMS. The most common causes of secondary RLS are iron deficiency, end-stage renal disease and pregnancy [1–3]. Peripheral neuropathies of different origin, diabetes mellitus and multiple sclerosis have been seen at higher than expected rates in RLS patients [13–15]. Moreover, RLS as a side-effect is ascribed to several drugs, and the majority of published papers focusing on this issue are case reports. An epidemiological study on the prevalence of RLS showed that the intake of selective serotonin re-uptake inhibitors is associated with an increased risk of RLS (odds ratio = 3 : 1). A recent prospective study addressed this problem for the class of second-generation antidepressants (ADs) [16]. Patients treated for the first time with an AD were prospectively evaluated with regard to the question of whether RLS occurred or pre-existing RLS worsened as a result of the AD. In 9% of patients, RLS was observed as a side-effect related to the AD treatment. This finding was most pronounced with mirtazapine, provoking or deteriorating RLS in 28% of patients. Of the patients who had no RLS before the start of treatment, 8% developed RLS during AD treatment and this side-effect occurred after a median of 2.5 days. Of the patients with pre-existing RLS, 13% experienced marked RLS deterioration. According to some authors [17], an important determinant of the clinical tolerability of ADs in RLS seems to be whether the patient has already been treated for RLS or not. If a patient has sufficiently been treated for RLS, he/she usually tolerates ADs. With regard to treatment for RLS, the development of validated rating scales and standardized diagnostic criteria have vastly improved the quality of RLS treatment trials. Several medications have shown outstanding efficacy; however, all of them provide only symptomatic relief rather than a real “curative” effect. Dopaminergic agents are considered first-line treatment for RLS [3,17]. Non-pharmacological treatments have rarely been investigated. 2. Non-pharmacological treatment There are only very few and not well-controlled studies on non-pharmacological treatments for RLS. A recent 12-week ran-
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domized controlled trial evaluated the effectiveness of an exercise programme on RLS [18]. Study participants were randomized to either exercise (a conditioning programme of aerobic and lower-body resistance training 3 days per week) or control groups. At the end of the 12 weeks, a significant improvement in RLS symptoms was observed in the exercise group compared with controls. In the management of RLS, it is important to inform the patient to maintain good sleep hygiene to prevent the development of insomnia, which is frequently observed. Indeed, some patients go to bed later at night and remain active during hours when their symptoms make sleep difficult, and some severe RLS patients may even change their working schedule for that purpose. Moreover, patients should avoid alcohol, caffeine and heavy meals in the evening since these may aggravate RLS symptoms. Improvement of RLS symptoms has been anecdotally reported with hot baths or application of something hot or cold, or performing tasks requiring a large amount of concentration and so keeping the patient’s mind alert [3]. Recently, a proof-of-concept study on cognitive behavioural therapy tailored to RLS showed favourable results in both medicated and unmedicated RLS patients [19]. Both groups took part in eight group sessions on a weekly basis (session of 90 min each). Subjective ratings of RLS severity, as well as quality of life and mental health status of the patients, had improved at the end of therapy and at follow-up 3 months later. These results suggest that psychological strategies may be included in an integrated treatment approach in RLS.
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from 85% after 2 years to 31% after a mean of 31 months [9,17]. The most frequent adverse effects of L -dopa reported in a large controlled trial were nausea (10.4%), headache (9.3%), fatigue (4.4%), and nasopharyngitis (4.4%). However, the most relevant clinical side-effect of L -dopa therapy is augmentation. Augmentation [9] is a phenomenon characterized by an earlier onset of symptoms by at least 4 hours or by an earlier onset between 2 and 4 hours plus at least one of the following compared with symptom status before treatment: (a) shorter latency to symptoms when at rest; (b) extension of symptoms to other body parts; (c) greater intensity of symptoms; or (d) shorter duration of relief from treatment. Augmentation is probably triggered by intense dopaminergic stimulation of the D1 receptor compared with the D2 and D3 receptors, predominantly at the spinal level. Iron deficiency and sleep deprivation may increase the risk of augmentation [9]. Prevalence rates of augmentation in open-label trials with L dopa range from 18.6% to 72% [22]. Recently, a study that employed a specific scale for measuring the phenomenon (Augmentation Severity Rating Scale, ASRS) showed augmentation in 36 of 60 (60%) patients treated for 6 months with L -dopa (median daily dose 300 mg; range, 50–500 mg) [23]. Increased severity of RLS and higher dosage of L -dopa are associated with higher risk of developing augmentation: maximum dosages of 300–400 mg should not be exceeded [17]. Mild augmentation could be treated by lower dosages divided for afternoon, evening, and at night, but in severe cases the medication should be discontinued. 3.2. Dopamine receptor agonists
3. Pharmacological treatment of idiopathic RLS The high prevalence of RLS does not necessarily mean that all patients should be treated with pharmacological therapy. Pharmacological treatment should be limited to those patients who suffer from clinically relevant RLS symptoms, including intermittent RLS with impaired sleep quality or quality of life [9,17]. All recent trials have focused the primary outcome measure on the International RLS Severity Scale (IRLS; a 10-item scale, each item with a score of 0 to 4: a total of 1 to 10 indicates mild; 11 to 20 moderate; 21 to 30 severe; and 31 to 40 very severe RLS) or polysomnographic sleep parameters (especially PLM index). According to evidence-based medicine criteria, dopaminergic medications should be the first-line therapy in RLS [20]. 3.1. L -dopa Several open-label studies documented the short-term efficacy of L -dopa given with a dopa-decarboxylase inhibitor [3]. Doses between 100 and 200 mg standard L -dopa improve RLS symptoms as measured on a visual analogue scale [9,17]. L -dopa is a shortacting medication and the immediate response without a long titration period is really appreciated by the patient. A positive response to this drug with the first dosage strongly supports the diagnosis of RLS [21]. However, a possible side-effect of L -dopa is morning rebound, characterized by the presence of RLS symptoms occurring de novo as a consequence of evening or night-time treatment. With L -dopa, it is also possible to observe a rebound of PLMS in the last part of the night when L -dopa is administered only at bedtime [3]. In rebound, the reappearance of symptoms is compatible with the timing of withdrawal from medication: indeed, the plasma half-life of L -dopa is very short (1–2 hours) and the beneficial effect rapidly decreases. If RLS persists in the second half of the night, an additional dose of slow-release L -dopa (100 mg) may be given in combination with standard L -dopa 1 hour prior to or at bedtime [17]. Some studies examined the long-term benefit of L -dopa and found various rates of persistent efficacy ranging
Several double-blind controlled studies have shown that both ergoline (cabergoline, pergolide) and non-ergoline (ropinirole, pramipexole, and rotigotine) dopamine receptor agonists are able to control RLS symptomatology (Table 1). There are insufficient data for other compounds, such as lisuride and bromocriptine. In short-term follow-up studies, the D2 receptor agonist bromocriptine was found effective in treating RLS and PLMS [9,17]. However, bromocriptine is frequently associated with severe adverse effects, especially nausea, responsible for withdrawal from bromocriptine shortly after the onset of treatment. Pergolide, another D2 receptor agonist was more extensively studied and its efficacy has been well-documented in short- and long-term follow-up studies [9,17]. Pergolide was also found superior to L -dopa in alleviating symptoms of RLS. In 28 patients treated for 416 days with pergolide, persistent efficacy was noted in 79% of patients but adverse effects were noted in 71%, including augmentation in 27% of cases [9,17]. Cabergoline, a long-acting D2 receptor agonist, was also used successfully to treat RLS [17,20]. An open long-term study showed that the beneficial effects of low-dose cabergoline (mean dosage = 2.2 mg) on RLS symptoms persist throughout a follow-up period up to 1 year [24]. The most common side-effects observed in open and double-blind studies are nausea, constipation, headache, and orthostatic hypotension [17]. No augmentation has been reported
Table 1 Dopamine agonists in RLS
Lisuride Bromocriptine Cabergoline Pergolide Pramipexole Ropinirole Rotigotine
Half-life (hours)
Initial dosage (mg)
Usual dosage range (mg)
2–3 3–8 65 7–16 8–12 6 Constant plasma levels (patch)
0.1 1.25 0.5 0.05 0.125 0.25 0.5 or 1
0.1–2 2.5–5 0.5–2 0.1–0.75 0.125–0.5 0.5–4 0.5–3
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in a single-blind 1-year study in a small number of RLS patients treated with cabergoline [25]. A more recent controlled study using the ASRS showed a rate of augmentation of 4% [20]. Retroperitoneal, pericardial and pleuropulmonary fibrosis are well known but rare complications of the treatment with ergoline dopamine receptor agonists. Recently, two studies showed that pergolide and cabergoline have a similar risk of inducing valvular heart disease and cardiac-valve regurgitation [26,27]. This possible side-effect has not been reported in controlled RLS trials. However, there are two case reports regarding the occurrence of pleuropulmonary fibrosis and valvular heart disease after pergolide treatment in RLS patients [28,29]. In recent years, two non-ergoline derivatives, pramipexole and ropinirole, have been extensively studied for RLS treatment. Montplaisir et al. [30] evaluated pramipexole, a full agonist with high affinity for the D3 receptor subtype, in a crossover placebocontrolled study. They found that the compound was very effective in treating RLS and in suppressing PLMS. Another recent double-blind placebo-controlled study [31] confirmed the efficacy of pramipexole (median dose 0.35 mg/day). Some recent long-term follow-up studies of patients treated with pramipexole [9,17,20] showed a sustained efficacy of the drug in more than 80% of RLS patients. Augmentation with pramipexole was reported in open trials in 8.5–39% of patients [17]. Some randomized placebo-controlled trials have shown that ropinirole is also effective in treating RLS [20]. In a flexible dosetitration polysomnographic trial, a mean dose of 1.8 mg ropinirole significantly reduced PLM and improved sleep parameters [32]. A long-term open-label study showed that ropinirole (mean dose 1.90 mg/day) maintained its therapeutic efficacy in 82% of RLS patients [33]. There were no reports of augmentation in the published studies, but the phenomenon was not systematically assessed. In the absence of comparative trials of pramipexole versus ropinirole, a recent meta-analysis compared the efficacy and tolerability of these two dopamine receptor agonists [34]. The direct meta-analysis confirmed superior efficacy for both treatments versus placebo in reducing RLS. Placebo comparisons showed a significantly higher incidence of nausea with pramipexole, whereas nausea, vomiting, dizziness and somnolence were significantly higher with ropinirole. The indirect comparison showed, with a probability of >95%, a superior reduction in mean IRLS score and significantly lower incidence of nausea, vomiting, and dizziness for pramipexole compared with ropinirole [34]. A first-night effect of pramipexole [35] and ropinirole [36] has been observed in RLS patients. A low dose of both drugs induces a significant effect on symptoms subjectively reported, as well as a significant improvement in PLMS. Sleepiness associated with sudden onset of sleep has been reported in patients with Parkinson’s disease (PD) treated with pramipexole and ropinirole. In RLS patients, sleepiness might be seen during treatment with dopamine receptor agonists but is much less problematic [3]; moreover, these compounds in RLS may, in contrast to PD, reduce the risk of sudden onset of sleep, probably due to their beneficial effect on sleep [37]. It has been suggested that striatal and limbic dysregulation in PD are putative factors in compulsive behaviours arising from dopamine receptor agonists. Recently, behavioural complications, such as pathological gambling and punding, have also been reported in some RLS patients undergoing dopaminergic treatment [38–41]. Rotigotine is a new non-ergoline agonist of D3, D2 and D1 dopamine receptors, with an almost 15-fold higher affinity for the D2 receptor than for the D1 receptor. In three placebocontrolled trials, transdermal rotigotine demonstrated significant improvement in RLS severity [42,41–44]. Transdermal 24-hour delivery of low-dose rotigotine (patch with 1–3 mg) may relieve
the night-time and daytime symptoms of RLS: the beneficial effects persist up to 6 months. To date, no signs of augmentation have been reported in the trials with rotigotine. Low rates of typical dopaminergic side-effects have been observed in patients who receive rotigotine. However, skin reactions, mostly mild or moderate, are often seen at the application site of the patch; the rate increases with increasing rotigotine dose and can be minimized by changing the application site daily [42–44]. 3.3. Non-dopaminergic treatments Several open-label and controlled clinical trials have evaluated the therapeutic effect of opioids in RLS and these compounds have long been known to successfully treat RLS [17]. Oxycodone administered at a mean daily dose of 11.4 mg both improved subjective ratings and decreased PLMS in 11 RLS patients, with evidence for decreased arousals and improved sleep efficiency [17,20]. A persistent effect of opioids was more recently reported in long-term follow-up studies [17,20]. Opioids may be prescribed in severe cases, especially to those unresponsive to other treatments. Although there is little evidence of tolerance or addiction to opioids in the RLS literature, the prescription of these compounds should be restricted to patients without a previous history of substance abuse. Interestingly, it has been reported that tramadol may cause augmentation [45]. Gabapentin is an anti-epileptic with multiple mechanisms of action, including inhibition of the alpha (delta) subunit of the sodium channel. A subjective improvement of RLS with gabapentin at doses of 300 to 2,400 mg a day has been reported in some openlabel trials and one placebo-controlled study [17,20]. Gabapentin produces few adverse effects except for mild daytime somnolence. An open clinical trial [46] compared the efficacy of gabapentin and ropinirole in patients with idiopathic RLS. This study showed that both compounds provided a similarly well-tolerated and effective treatment for RLS and PLMS. In patients who have developed adverse effects with dopaminergic medications, gabapentin may be a valuable alternative [17]. Other anticonvulsants, such as carbamazepine and valproic acid, have been evaluated in RLS but seem to be less effective than gabapentin [17]. Despite their past widespread use, there is little data to support the use of benzodiazepines for RLS. Several studies showed that clonazepam, nitrazepam, lorazepam and temazepam improve the quality of sleep, reduce PLMS and /or PLMS associated with arousals in patients with RLS. However, the therapeutic effects of benzodiazepines on subjective ratings of RLS symptoms were either modest or non-significant [3]. Therefore benzodiazepines are mostly used to improve sleep continuity in patients with RLS. A recent paper [47] evaluated the effect of hydrocortisone infusion on RLS symptoms. A pathophysiological relationship between corticosteroid secretion and RLS could be hypothesized since plasma cortisol levels display a morning peak, afternoon decline, and nadir around midnight: an inverse temporal course is exactly observed for RLS symptoms. In a 1-week double-blind placebo-controlled study, Hornyak and co-workers [47] found an improvement in symptoms in 5 of the 10 patients treated by a single dose of intravenous hydrocortisone 40 mg in the evening. On the other hand, in RLS the improvement of symptoms with physical activity may be associated with the known changes in hypothalamic-pituitary-adrenal axis activity of cortisol levels that increase during physical exercise. Moreover, cortisol has been described as enhancing the secretion of dopamine in the central nervous system.
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3.4. Treatment of secondary RLS In RLS patients with iron deficiency, iron supplementation has been shown to improve RLS [17]. When a patient’s ferritin level is <45–50 μg/L, oral iron treatment is indicated as supplemental treatment. Oral iron treatment can be ferrous sulphate 325 mg, or its equivalent, with vitamin C 100–200 mg, taken twice a day, preferably on an empty stomach if the iron is tolerated. Since iron is not absorbed very well in the gastrointestinal tract, treatment with intravenous iron infusion could be more effective, but anaphylaxis is a possible adverse event after administration of intravenous iron. A recent randomized, double-blind, placebo-controlled trial of intravenous iron sucrose (1,000 mg/day) failed to demonstrate the significant improvement in RLS reported in prior open-label studies [48]. However, patients with normal ferritin levels were also included in that study. Another randomized double-blind placebo-controlled trial with intravenous iron sucrose (1,000 mg/day) evaluated RLS patients with serum ferritin <45 μg/L [49]. This study showed a lack of superiority of iron sucrose compared with saline at 11 weeks, but found evidence that iron sucrose reduced RLS symptoms both in the acute phase (7 weeks) and during long-term follow-up (12 months). The RLS seen in patients on dialysis is often severe. Compared with idiopathic RLS, series show similar or increased overall severity, increased PLMS, increased wakeful leg movements, and a more rapid progression [50]. Dialysis does not improve RLS. In RLS patients with renal insufficiency, successful kidney transplant may lead to complete remission of RLS within days or weeks [51]. Complete remission of symptomatology is also usually observed after delivery in patients with pregnancy-related RLS [52]. Some investigators have suggested that gabapentin [20] or pregabalin [53] may be preferentially effective in the treatment of secondary RLS for patients with neuropathy. It is well known that these compounds improve neuropathic pain. A combination of sedative and sensory modulating actions of gabapentin and pregabalin might explain their effect in RLS. However, these compounds should be further investigated in randomized placebocontrolled trials. 4. Conclusion As with many chronic disorders, RLS varies considerably in both symptom severity and degree of impact on health and wellbeing. Preliminary studies of non-pharmacological approaches to RLS treatment have shown positive results and encourage further trials. In patients with mild RLS, good sleep hygiene should be recommended. Patients should be advised to avoid alcohol, caffeine and heavy meals before going to sleep. Bedtime hours should be regular and activity should be gradually reduced in the evening. Pharmacological treatment should be limited to those patients who suffer from clinically relevant RLS symptoms. Treatment on demand is a clinical need in certain RLS patients, but unfortunately intermittent therapy for RLS has not been investigated in clinical trials. Some pharmacological data and clinical experience suggest that L -dopa 100 mg or pramipexole 0.25 mg may be used for intermittent therapy during daytime or at sleep onset. Most patients with idiopathic RLS respond robustly to dopaminergic agents. The best strategy is to start pharmacological therapy cautiously and at the lowest recommended doses. L -dopa improves RLS, but is associated with a high incidence of symptom rebound and augmentation. Rebound with L -dopa is related to its short half-life. Augmentation, mainly characterized by the occurrence of RLS symptoms earlier in the day, is a phenomenon less frequently observed with dopamine receptor agonists. Since ergot-derived
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compounds can cause pleural, pericardial, and retroperitoneal fibrosis, non-ergot dopamine receptor agonists are preferred. Due to their tolerability and half-life, the D3 receptor agonists pramipexole and ropinirole have become the first-line treatment in RLS. Recent papers have shown the efficacy of transdermal rotigotine in the treatment of RLS: stable drug concentrations over 24 hours seem to be a favourable strategy to also cover daytime symptoms and probably avoid augmentation. Other treatment (second-line) options for RLS include gabapentin and opioids. Gabapentin may be used if dopamine receptor agonists are not tolerated or fail. Opioids are a highly effective therapy in advanced and severe forms of RLS. High-dose intravenous iron could be promising, but is still an experimental approach. In recent years, some studies have shown that there is a significant association between certain health factors and RLS. In severe RLS, a significant relationship with health problems such as cardiovascular diseases and hypertension has been found [54–56]. Sleep loss and the presence of PLMS might explain the increased cardiovascular risk in RLS patients, and this increased risk may justify the pharmacological treatment of moderate/severe RLS cases. Conflict of interest Luigi Ferini-Strambi has received honoraria for serving on scientific advisory boards for Boehringer-Ingelheim, UCB-Schwarz Pharma, GlaxoSmithKline, Sanofi-Aventis, and Transcept Pharmaceuticals. Mauro Manconi has no potential conflict of interest to declare. References [1] American Academy of Sleep Medicine. International Classification of Sleep Disorders. Diagnostic and Coding Manual. Westchester, IL: American Academy of Sleep Medicine; 2005. [2] Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institute of Health. Sleep Med 2003; 4:101–19. [3] Montplaisir J, Allen R, Walters A, Ferini-Strambi L. Restless legs syndrome and periodic limb movements during sleep. In: Kryger MH, Roth T, Dement WC, editors. Principles and Practice of Sleep Medicine. 4th ed.. Philadelphia: Elsevier, 2005. p. 839–52. [4] Michaud M, Dumont M, Selmaoui B, Paquet J, Fantini ML, Montplaisir J. Circadian rhythm of restless legs syndrome symptoms: relationship with biological markers. Ann Neurol 2004;55:372–80. [5] Qu S, Le W, Zhang X, Xie W, Zhang A, Ondo WG. Locomotion is increased in a11-lesioned mice with iron deprivation: a possible animal model for restless legs syndrome. J Neuropathol Exp Neurol 2007;66:383–8. [6] Dean T Jr, Allen RP, O’Donnell CP, Earley CJ. The effects of dietary iron deprivation on murine circadian sleep architecture. Sleep Med 2006;7:634– 40. [7] Allen RP, Earley CJ. The role of iron in restless legs syndrome. Mov Disord 2007;22 Suppl 18:S440–8. [8] Coleman RM. Periodic movements in sleep (nocturnal myoclonus) and restless legs syndrome. In: Guilleminault C, editor. Sleeping and waking disorders: indications and techniques. Menlo Park, CA: Addison-Wesley; 1982. p. 265– 95. [9] Trenkwalder C, Högl B, Winkelmann J. Recent advances in the diagnosis, genetics and treatment of restless legs syndrome. J Neurol 2009;256:539–53 [10] Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005;165:1286–92. [11] Winkelmann J, Schormair B, Lichtner P, Ripke S, Xiong L, Jalilzadeh S, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet 2007;39:1000–6. [12] Stefansson H, Rye DB, Hicks A, Petursson H, Ingason A, Thorgeirsson TE, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2007;357:639–47. [13] Gemignani F, Brindani F. Restless legs syndrome associated with peripheral neuropathy. Eur J Neurol 2007;14:e9–e10.
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