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First night efficacy of pramipexole in restless legs syndrome and periodic leg movements
Sleep Medicine 8 (2007) 491–497 www.elsevier.com/locate/sleep
Original article
First night efficacy of pramipexole in restless legs syndrome and periodic leg movements Mauro Manconi a,*, Raffaele Ferri b, Marco Zucconi a, Alessandro Oldani a, Maria Livia Fantini a, Vincenza Castronovo a, Luigi Ferini-Strambi a a
Sleep Disorders Center, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Vita-Salute University, Milan, Italy b Sleep Research Centre, Department of Neurology I.C. Oasi Institute (IRCCS), Troina, Italy Received 14 July 2006; received in revised form 19 September 2006; accepted 14 October 2006 Available online 18 May 2007
Abstract Objective: Restless legs syndrome (RLS) seems to improve immediately after a single dose of dopamine-agonists (DA). The aim of the present study was to investigate the acute effects of a low standard dose of pramipexole in RLS drug-naı¨ve patients. Methods: A single-blind placebo-controlled study in 32 consecutive idiopathic RLS de-novo patients was carried out. Patients who met the standard criteria for RLS, with a PLMS index greater than 10 as well as an RLS rating scale score greater than 20 underwent clinical and neurophysiological evaluation, hematological screening and two consecutive full-night polysomnographies. On the second night, all patients received 0.25 mg of pramipexole or placebo at 9:00 p.m. Acute symptom response was assessed by a visual analogical scale (VAS). Results: Eighteen patients received pramipexole and 14 patients received placebo. Compared to placebo, the single low dose (0.25 mg) of pramipexole significantly improved RLS symptoms (VAS: from 7.4 ± 1.68 to 1.3 ± 1.62, p < 0.00001) and strongly reduced PLMS index (from 45.8 ± 33.56 to 9.4 ± 11.40, p < 0.0002). A significant increase in the percentage of stage 2 non-rapid eye movement (NREM) sleep was also observed in the pramipexole group (from 38.7 ± 10.50 to 50.6 ± 12.13, p < 0.02). Conclusions: A low dose of pramipexole was effective in treatment-naı¨ve patients with RLS from the first night of administration. These results support a direct involvement of the dopaminergic system in RLS pathogenesis and might have important implications for a possible future pramipexole administration on-demand, as well as for a pharmacological test to confirm diagnosis in clinically complex cases. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Restless legs syndrome; Periodic leg movements; Pramipexole; Sleep; Dopamine; On-demand Therapy
1. Introduction Restless legs syndrome (RLS) is a common sleep-related movement disorder characterized by uncomfortable sensations in the limbs appearing or becoming worse at evening/night rest and alleviated by motor activity [2]. Most RLS patients present periodic limb movements during sleep (PLMS) [3]. The diagnosis of *
Corresponding author. Tel.: +39 2 2643 3358; fax: +39 2 2643 3394. E-mail address: [email protected] (M. Manconi). 1389-9457/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2006.10.008
RLS is currently based on the ability of the patient to describe his or her symptoms and of the physician to match these symptoms to the clinical diagnostic criteria [2,3]. As in other neurological diseases not associated with objective reliable markers, the response to standard treatments often helps in confirming the diagnostic assessment. Because of their remarkable efficacy and tolerability, dopamine-agonists are nowadays considered the first choice for treatment of RLS [4]. At the present time, carbidopa/levodopa is not frequently used because of its short half-life and the consequent high incidence of
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symptom rebound and/or augmentation [5]. Furthermore, typical side effects associated with ergot-derivate molecules partially limit the use of bromocriptine, pergolide and cabergoline, and often require a concomitant medication with the peripheral dopamine-antagonist domperidone [6]. Due to their tolerability and half-life, low evening doses of the D3-agonists pramipexole and ropinirole have become the first of line treatment in RLS [4]. However, follow-up studies demonstrated an augmentation effect also following the use of D3 non-ergoline agonists in about one-third of patients, appearing after at least six months of therapy [7]. Some controlled studies, supported by polysomnographic (PSG) recordings, proved that ropinirole and pramipexole are noticeably effective in reducing both symptoms and PLMS [8–10,1,8,11]. In one of these studies [10], the efficacy of ropinirole has been demonstrated after a single drug administration in RLS patients not naı¨ve to treatment. Response to dopaminergic medications, together with positive family history and presence of PLMS, are considered to be supportive criteria for the diagnosis of RLS [4]. In clinical practice, it is common that pramipexole is effective for RLS from the first days of treatment. These empirical data have never been demonstrated by an experimental procedure. The aim of the present investigation was to evaluate the initial response to a standard low dose of pramipexole, in a cohort of drug-naı¨ve patients affected by idiopathic RLS, by means of a controlled clinical PSG study.
10 during the baseline PSG (see below). Patients with an apnea/hypopnea index >5 were excluded. Results of neurological examination in all patients were unremarkable. Routine blood tests (including serum iron and ferritin, B12 vitamin, and folate), as well as electromyography (EMG) and electroneurography of the lower limbs, were also normal. Patients suffering from known causes of secondary RLS (e.g., renal failure, anemia with iron-deficiency, pregnancy, rheumatoid arthritis, or clinical peripheral neuropathy), other sleep disorders (e.g., narcolepsy, parasomnia and sleep breathing disorder), other movement disorders, or any medical conditions that would affect the assessment of RLS (e.g., fibromyalgia syndrome) were also excluded. Subjects were randomly assigned to two groups (treated and placebo) and underwent an adaptation night in the lab, followed by two nocturnal PSG recordings. No medication was administered before the first night recording (baseline). Before the second night of recording, subjects included in the treatment group received a single oral dose of 0.25 mg pramipexole at 9:00 p.m., while the remaining patients received placebo. All patients gave their written consent for these procedures and were unaware of the content (drug or placebo) of the medication. In the morning, after each PSG recording, all patients evaluated the severity of their previous night symptoms by means of the Visual Analogical Scale (VAS) [12]. The local ethical committee approved the study. 2.2. Nocturnal polysomnographic (PSG) studies
2. Subjects and methods 2.1. Subjects A prospective single-blind controlled study was carried out in consecutive subjects affected by idiopathic RLS. According to the International RLS Study Group, the minimal criteria for the diagnosis of RLS were leg restlessness, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs; beginning or worsening of this unpleasant sensation during rest or inactivity such as lying or sitting; partial or total relief of the unpleasant sensations by movement; and worsening or occurrence of the unpleasant sensations in the evening or night, compared to daytime [11]. To be included in the study, the mean frequency of symptoms during the last six months had to be greater than two times per week, with a score of at least 20 on the International RLS Study Group rating scale (corresponding to severe RLS) at the time of enrollment [11]. Only patients free of medication at the time of the evaluation, and never previously treated for RLS (dopaminergic agents, benzodiazepines, opioids and anticonvulsants), were included. Additional inclusion criteria were being between 18 and 70 years old and having a PLMS index greater than
Nocturnal PSGs were carried out after a night of adaptation in a standard sound-attenuated (noise level to a maximum of 30 dB nHL) sleep laboratory room. Subjects were not allowed to drink caffeinated beverages six hours before the beginning of each PSG and were allowed to sleep until their spontaneous awakening in the morning. Lights-out time was based on the individual’s usual bedtime and ranged between 10:30 and 11:30 p.m. The following signals were recorded: electroencephalogram (EEG) (six channels, including C3 or C4 and O1 or O2, referred to the controlateral mastoid); electrooculogram (EOG; electrodes placed 1 cm above the right outer cantus and 1 cm below the left outer cantus and referred to the mastoid); EMG of the submentalis muscle; EMG of the right and left tibialis anterior muscles (bipolar derivations with two electrodes placed 2 cm apart on the anterior tibialis muscle of each leg, impedance was kept less than 10 KX, according to the American Sleep Disorders Association (ASDA) scoring criteria) [13]; and electrocardiogram (ECG; one derivation). Sleep signals were sampled at 200 Hz and stored on hard disk in European data format (EDF) [14] for further analysis. EMG signals, in particular, were digitally band-pass filtered at 10–100 Hz, with a notch filter
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at 50 Hz. The sleep respiratory pattern of each patient was monitored using oral and nasal airflow thermistors and/or nasal pressure cannula, thoracic and abdominal respiratory effort strain gauge and by monitoring oxygen saturation (pulse-oximetry). This was performed in all subjects in a previous recording (within 1 week) or during the study recording. 2.3. Sleep scoring and detection of leg movements Prior to any recording, we verified that the EMG amplitude recorded from the two tibialis anterior muscles was below 2 lV at rest and exceeded 7–10 lV for small voluntary dorsiflexions of the foot. EMG amplitude at maximal deflection was also measured for the application of the ASDA scoring criteria [13]. Sleep stages were scored following standard criteria [15] on 30-s epochs using the sleep analysis software Hypnolab 1.2 (SWS Soft, Italy). Leg movements (LM) during sleep were first detected by the same software, which allows for computer-assisted detection. With this software, detection of LMs is performed using a human-supervised automatic approach controlled by the scorer following ASDA criteria [13]. The performance of this system has been recently evaluated and validated [16], but in this study one scorer visually edited, epoch by epoch, the detections proposed by the automatic analysis, before computing a final result. In particular, the total LM index was calculated to represent the total number of LM per hour of sleep. The PLMS index was calculated as the number of LM included in a series of four or more, separated by more than five and less than 90 s, per hour of sleep. Analysis included the PLMS index of the entire night, and separately of REM and NREM sleep, as well as the total number of LMs and number of PLMS sequences. Finally, the change in PLMS index observed between the baseline and the treatment nights was normalized for its baseline value by means of the calculation of the following ratio: ðbaseline PLMS index treatment PLMS indexÞ=baseline PLMS index that will be indicated here as ‘‘PLMS change index’’. Mathematically, this index can vary from +1 (complete disappearance of PLMS in the treatment night) to 1 (appearance of PLMS in the treatment night).
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2.4. Statistical analysis The comparison between the different sleep and LM parameters obtained before and after the administration of pramipexole or placebo was carried out by means of the factorial analysis of variance (ANOVA), with ‘‘group’’ (pramipexole or placebo) and ‘‘night’’ (baseline or treatment) as factors, which was followed by post hoc analysis for the individual group or night comparisons. For this analysis, the significance level was set at p < 0.05 and the commercially available Statistica software package (StatSoft, Inc., 2001. STATISTICA data analysis software system, version 6. www.statsoft.com) was used. 3. Results Thirty-two consecutive untreated patients were included in this study (mean age 58.4 ± 11.6, 9 males and 23 females); 18 patients received pramipexole and 14 were given placebo. Table 1 reports the demographic data of the patients and the results of the subjective evaluation of the severity of the RLS symptoms measured before treatment by the International RLS Study Group rating scale. One patient treated with pramipexole and another who was administered placebo reported mild morning nausea; no other significant side effects were reported by any of the rest of the patients. The mean VAS score before and after treatment changed from 7.4 ± 1.68 standard deviation (SD) to 1.3 ± 1.62 SD (p < 0.00001) in the pramipexole group, and from 6.8 ± 1.72 SD to 5.4 ± 2.33 SD (not significant) in the placebo group. The VAS score improved in all subjects and reached the value of 0 in 10 out of 18 patients treated with pramipexole, while it did not change in two patients and became worse in another three who took the placebo. Table 2 shows the comparison between the different sleep scoring parameters obtained before and after the administration of pramipexole or placebo. In this table, the ANOVA was significant only for the factor ‘‘night’’ and for the percentage of sleep stage 2 which was increased in the pramipexole treatment night. Other parameters, in addition, such as time in bed and sleep efficiency, tended to show evident modifications in the pramipexole treatment night but these differences did not reach statistical significance.
Table 1 Demographic data of the patients and results of the subjective evaluation of RLS symptom severity, measured before treatment by the International RLS Study Group rating scale
Total Pramipexole group Placebo group
Males (n)
Females (n)
Age, mean (SD)
IRLSSG score, mean (SD)
9 4 5
23 14 9
58.4 (11.6) 59.8 (11.2) 56.6 (12.3)
27.0 (4.85) 27.3 (5.19) 26.6 (4.55)
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Table 2 Comparison between the different sleep scoring parameters obtained before and after the administration of pramipexole or placebo 1st Night Pramipexole Mean SD TIB (min) 512.9 SPT (min) 473.4 TST (min) 343.5 SOL (min) 27.1 FRL (min) 134.4 SS/hour 11.0 AWN/hour 4.8 Sleep efficiency, % 65.6 WASO (min) 129.9 S1 (min) 26.1 S2 (min) 184.4 SWS (min) 66.2 REM (min) 66.8 WASO, % 29.7 S1(%) 5.5 S2 (%) 38.7 SWS (%) 13.1 REM (%) 13.1
100.02 102.64 131.20 34.98 79.45 4.23 2.95 21.00 78.27 24.01 66.79 41.04 41.38 19.73 5.02 10.50 7.64 7.69
2nd Night Placebo
Pramipexole
ANOVA Placebo
Post hoc Baseline vs. Treatment Pramipexole vs. Placebo
Mean SD
Mean SD
Mean SD
Night Group Pramipexole Placebo Baseline Treatment
509.3 473.3 378.4 22.7 100.5 12.3 4.6 74.3 94.9 30.5 199.8 69.7 78.5 19.8 6.3 41.9 15.4 16.5
525.6 499.9 414.3 12.4 140.8 14.2 5.7 78.9 85.6 33.3 253.6 66.2 61.3 17.2 6.6 50.6 13.5 12.2
481.6 453.3 354.1 17.3 122.2 12.4 4.6 74.3 99.2 24.8 191.9 74.0 63.4 21.0 5.5 43.4 16.3 13.8
NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS 0.02 NS NS
89.97 87.87 87.60 24.06 40.93 3.35 2.44 10.02 61.31 19.71 66.71 37.66 29.39 11.99 3.72 10.70 9.70 5.23
44.87 45.76 57.86 8.14 99.15 4.48 3.71 8.36 40.16 26.47 66.01 35.99 28.48 7.99 4.93 12.13 7.84 5.18
97.79 93.72 76.44 21.93 67.81 4.16 2.33 11.07 71.27 22.74 46.61 31.60 21.46 12.05 4.64 10.85 6.46 3.98
NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS
0.0005
NS
TIB, time in bed; SPT, sleep period time; TST, total sleep time; SOL, sleep onset latency; FRL, first REM latency; SS, stage shifts; AWN, awakenings number; WASO, wakefulness after sleep onset;S1, stage 1; S2, stage 2; SWS, slow-wave sleep; REM, REM sleep.
Table 3 reports the comparison between the different LM scoring parameters obtained before and after the administration of pramipexole or placebo. In this comparison, whole-night PLMS index and NREM sleep total LM and PLMS index were significantly lower during the pramipexole treatment night than during the baseline recording. The same parameters showed a statistically significant difference between the two patient groups, after treatment but not at baseline. No detectable changes followed the placebo treatment. Fig. 1 shows, for example, the hypnogram of the baseline and treatment nights in a patient who was administered pramipexole; in this figure it is possible to see the important changes in LM activity (a detail is shown in the upper panel, in baseline conditions) and of sleep structure occurring after treatment. Fig. 2 reports the individual and average (with SD) values of the PLMS change index in the two groups of patients; it is possible to notice that the pramipexole group shows significantly higher values of this index than the placebo group (p < 0.00001). Moreover, 13 out of 18 subjects receiving pramipexole show a PLMS change index higher than the highest observed in the placebo group (0.726); the same figure also shows the individual values of the PLMS index in both groups of patients, at baseline and after treatment. Finally, no significant correlation was found between the PLMS change index and the magnitude of VAS change for subjects receiving pramipexole (Pearson r = 0.140) or placebo (Pearson r = 0.106).
4. Discussion The acute administration of a low dose (0.25 mg) of pramipexole in treatment-naı¨ve, idiopathic, severe RLS patients markedly improved the symptoms from the first night of therapy in all treated subjects, leading to a complete disappearance of symptoms in more than half of the cases. The most remarkable objective effect of pramipexole is represented by the immediate drop of the PLMS index, clearly evident in all subjects who took the drug. Despite the inclusion of severe RLS patients with PLMS, our unambiguous results may be also an effect of the fact that only patients who had never been treated for RLS previously were included. At the same time it is important to note that, as expected because of their occurrence during sleep, PLMS do not seem to be influenced by the placebo effect [11]. The abrupt response of symptoms and PLMS to pramipexole stands for a possible common dopaminergic origin of both of these pathological phenomena [17]. Our results support the hypothesis of a direct involvement of D3 subtype receptors in the pathogenesis of PLMS and RLS symptoms [18–20]. Pramipexole is a potent dopamine auto-receptor agonist which interacts with dopamine G protein-coupled D2 subfamily receptors (D2, D3, and D4 subtypes) showing a weaker bind to D1 subfamily receptors (D1 and D5 subtypes) and almost absent to adrenergic or serotonergic receptors [21]. Furthermore, pramipexole has a preferential affinity to D3 receptors with a selectivity 15 times more potent at D3 than D2
0.0003 0.0002
0.00007 0.00005
NS NS
NS NS
NS NS
NS NS
0.014 0.013 NS 0.036 NS 37.69 36.79 4.44 58.4 48.8 10.5 12.25 11.40 7.79 19.3 9.4 7.1 25.03 25.73 5.86 51.1 42.3 11.9 54.3 45.8 11.4 Total Total LM index PLMS index PLMS Sequence number
34.61 33.56 4.89
35.6 24.3 REM sleep Total LM index PLMS index
40.55 43.72
27.1 15.9
17.60 17.11
17.4 3.8
8.89 4.66
32.0 21.4
27.61 31.62
NS NS
NS NS
0.0002
0.0003 0.00007 0.004 0.004 0.037 0.021 39.21 37.94 64.2 55.0 14.15 13.12 19.6 10.4 27.94 28.63 57.4 49.2 34.47 32.84 58.1 50.4
Night SD Mean SD SD
SD
Mean Mean Mean
NREM sleep Total LM index PLMS index
Tretament Baseline Placebo Pramipexole Group
Post hoc
Baseline vs. Treatment
ANOVA Pramipexole
Placebo 2nd Night
Pramipexole Placebo
1st Night
Table 3 Comparison between the different scoring parameters for leg movements, obtained before and after the administration of pramipexole or placebo
Pramipexole vs. Placebo
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receptors [22]. D3 receptors appear to be concentrated in the limbic system, which is more related to cognitive aspects, and in the dorsal horns and intermediolateralgray matter of the spinal cord, likely to be involved in nociceptive modulation [23–26]. Spinal D3 receptors receive dopaminergic projections from the A11 nuclei, located within the lateral hypothalamus, which are suspected to play a role in the pathogenesis of RLS, and are closely related to the central circadian pacemaker of the suprachiasmatic nucleus [27]. In comparison to the effect on the subjective RLS components and on PLMS, the pharmacological effect on sleep macrostructure is less clear-cut but leans toward being a general improvement of hypnic parameters. From a panoramic vision of the PSG results, a tendency towards a quantitative sleep improvement (sleep effiency, total sleep time), especially for the light NREM stages, after acute pramipexole treatment, becomes evident. Part of these results did not reach statistical significance probably because of the high variance of the data. Interestingly, this rise in sleep quantity does not seem to be accompanied by a similar improvement in sleep continuity, with a propensity toward sleep fragmentation (increased number of awakenings/hour and stage shifts/hour) and an inefficacy in consolidating slow wave sleep. Probably, a longer period of treatment would be necessary for a more effective stabilization of sleep continuity. Moreover, PLMS might not be directly responsible for the instability in EEG microstructure and the disappearance of LMs is not automatically followed by a similar reduction in sleep fragmentation indexes. Saletu et al. [10] performed an acute (night-to-night) treatment evaluation in RLS patients by using 0.5 mg of ropinirole and found a significant ‘‘decrease in arousals due to PLMS, but an increase in spontaneous arousals after medication’’. This effect may also be interpreted as a selective action of ropinirole on PLMS, without a direct influence on the electro-cortical arousal activity that remains unchanged after treatment. The demonstration of an immediate efficacy of ropinirole and pramipexole is extremely important, not only because it is an obvious benefit to patients able to obtain rapid therapeutic results, but also because it opens the doors to two other possibly crucial drug applications, already discussed, in the near future for idiopathic RLS: on-demand therapy and the use of a standard single dopaminergic agent as a diagnostic ex-juvantibus test [28,29]. On-demand therapy may have significant results for patients with moderate or intermittent symptoms and for patients (treated and untreated) who are going to face forced immobility for a long time, such as in air, train or car travel, social events during the evening or sedentary working postures. In these cases, it is recommended that patients take the drug about 40– 60 min before the onset of the desired therapeutic window and choose middle/short half-life dopamine-agonists
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Fig. 1. Examples of the hypnogram at baseline and treatment nights (bottom panels) in a patient who was administered pramipexole; a short PSG segment of the baseline recording is shown in the top panel, for example. Abbreviations: LOC, ROC, left and right electro-oculogram; A1, A2, left and right earlobes; ECG, electrocardiogram; W, wakefulness; R, REM sleep; S1, S2, S3, S4, sleep stages 1, 2, 3, and 4.
Fig. 2. Individual and average (with S.D., whiskers) values of the PLMS change index in the two groups of patients (middle panel); individual values of the PLMS index in patients treated with pramipexole (left panel) and in those treated with placebo (right panel), at baseline and after treatment.
that do not need a pre-medication [28]. Regarding the second possible application, notwithstanding the fact that all of our patients showed an improvement in PLMS and symptoms (high sensitivity), the diagnostic value of a single-shot drug test might be decreased by the existence of false responders (low specificity), similarly to patients who show improved PLMS index or symptoms as a result of physiological night-to-night variability. We must also note that a possible limit of our
study was the absence of a longer period of baseline evaluation. On the other hand, a diagnostic test might be useful even if it can only exclude the diagnosis of RLS in the case of worsening of PLMS and/or symptoms; in fact, we never observed in our study an increase in PLMS index in subjects treated with pramipexole. The real feasibility of this hypothetical test should be also evaluated on the basis of cost, because the patients need to undergo two consecutive full-night PSG studies;
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however, this might be acceptable in consideration of long-term therapy needed in RLS. Moreover, the repeated application of the Suggested Immobilization Test instead of the full-night PSG could reduce diagnostic costs and time of execution [30]. In conclusion, our investigation demonstrates the immediate effectiveness and the excellent tolerability of a low standard dose of pramipexole in RLS patients, suggesting interesting pathogenetic speculations and important consequences on clinical practice for a possible on-demand treatment. The use of pramipexole in a diagnostic test needs further evidence in terms of reliability and suitability. References [1] Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003;4:101–19. [2] Walters AS. Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov Disord 1995;10:634–42. [3] Thorpy MJ. New paradigms in the treatment of restless legs syndrome. Neurology 2005;64:S28–33. [4] Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep 1996;19:205–13. [5] Walters AS, Hening WA, Kavey N, Chokroverty S, Gidro-Frank S. A double-blind randomized crossover trial of bromocriptine and placebo in restless legs syndrome. Ann Neurol 1988;24:455–8. [6] Ondo W, Romanyshyn J, Vuong KD, Lai D. Long-term treatment of restless legs syndrome with dopamine agonists. Arch Neurol 2004;61:1393–7. [7] Allen R, Becker PM, Bogan R, Schmidt M, Kushida CA, Fry JM, et al. Ropinirole decreases periodic leg movements and improves sleep parameters in patients with restless legs syndrome. Sleep 2004;27:907–14. [8] Manconi M, Casetta I, Govoni V, Cesnik E, Ferini-Strambi L, Granieri E. Pramipexole in Restless Legs syndrome. Evaluation by suggested immobilization test. J Neurol 2003;250:1494–5. [9] Saletu M, Anderer P, Saletu B, Hauer C, Mandl M, Oberndorfer S, et al. Sleep laboratory studies in restless legs syndrome patients as compared with normals and acute effects of ropinirole. 2. Findings on periodic leg movements, arousals and respiratory variables. Neuropsychobiology 2000;41:190–9. [10] Saletu M, Anderer P, Saletu-Zyhlarz G, Hauer C, Saletu B. Acute placebo-controlled sleep laboratory studies and clinical follow-up with pramipexole in restless legs syndrome. Eur Arch Psychiatry Clin Neurosci 2002;252:185–94. [11] Walters AS, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2003;4:121–32.
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Original article
First night efficacy of pramipexole in restless legs syndrome and periodic leg movements Mauro Manconi a,*, Raffaele Ferri b, Marco Zucconi a, Alessandro Oldani a, Maria Livia Fantini a, Vincenza Castronovo a, Luigi Ferini-Strambi a a
Sleep Disorders Center, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Vita-Salute University, Milan, Italy b Sleep Research Centre, Department of Neurology I.C. Oasi Institute (IRCCS), Troina, Italy Received 14 July 2006; received in revised form 19 September 2006; accepted 14 October 2006 Available online 18 May 2007
Abstract Objective: Restless legs syndrome (RLS) seems to improve immediately after a single dose of dopamine-agonists (DA). The aim of the present study was to investigate the acute effects of a low standard dose of pramipexole in RLS drug-naı¨ve patients. Methods: A single-blind placebo-controlled study in 32 consecutive idiopathic RLS de-novo patients was carried out. Patients who met the standard criteria for RLS, with a PLMS index greater than 10 as well as an RLS rating scale score greater than 20 underwent clinical and neurophysiological evaluation, hematological screening and two consecutive full-night polysomnographies. On the second night, all patients received 0.25 mg of pramipexole or placebo at 9:00 p.m. Acute symptom response was assessed by a visual analogical scale (VAS). Results: Eighteen patients received pramipexole and 14 patients received placebo. Compared to placebo, the single low dose (0.25 mg) of pramipexole significantly improved RLS symptoms (VAS: from 7.4 ± 1.68 to 1.3 ± 1.62, p < 0.00001) and strongly reduced PLMS index (from 45.8 ± 33.56 to 9.4 ± 11.40, p < 0.0002). A significant increase in the percentage of stage 2 non-rapid eye movement (NREM) sleep was also observed in the pramipexole group (from 38.7 ± 10.50 to 50.6 ± 12.13, p < 0.02). Conclusions: A low dose of pramipexole was effective in treatment-naı¨ve patients with RLS from the first night of administration. These results support a direct involvement of the dopaminergic system in RLS pathogenesis and might have important implications for a possible future pramipexole administration on-demand, as well as for a pharmacological test to confirm diagnosis in clinically complex cases. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Restless legs syndrome; Periodic leg movements; Pramipexole; Sleep; Dopamine; On-demand Therapy
1. Introduction Restless legs syndrome (RLS) is a common sleep-related movement disorder characterized by uncomfortable sensations in the limbs appearing or becoming worse at evening/night rest and alleviated by motor activity [2]. Most RLS patients present periodic limb movements during sleep (PLMS) [3]. The diagnosis of *
Corresponding author. Tel.: +39 2 2643 3358; fax: +39 2 2643 3394. E-mail address: [email protected] (M. Manconi). 1389-9457/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2006.10.008
RLS is currently based on the ability of the patient to describe his or her symptoms and of the physician to match these symptoms to the clinical diagnostic criteria [2,3]. As in other neurological diseases not associated with objective reliable markers, the response to standard treatments often helps in confirming the diagnostic assessment. Because of their remarkable efficacy and tolerability, dopamine-agonists are nowadays considered the first choice for treatment of RLS [4]. At the present time, carbidopa/levodopa is not frequently used because of its short half-life and the consequent high incidence of
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symptom rebound and/or augmentation [5]. Furthermore, typical side effects associated with ergot-derivate molecules partially limit the use of bromocriptine, pergolide and cabergoline, and often require a concomitant medication with the peripheral dopamine-antagonist domperidone [6]. Due to their tolerability and half-life, low evening doses of the D3-agonists pramipexole and ropinirole have become the first of line treatment in RLS [4]. However, follow-up studies demonstrated an augmentation effect also following the use of D3 non-ergoline agonists in about one-third of patients, appearing after at least six months of therapy [7]. Some controlled studies, supported by polysomnographic (PSG) recordings, proved that ropinirole and pramipexole are noticeably effective in reducing both symptoms and PLMS [8–10,1,8,11]. In one of these studies [10], the efficacy of ropinirole has been demonstrated after a single drug administration in RLS patients not naı¨ve to treatment. Response to dopaminergic medications, together with positive family history and presence of PLMS, are considered to be supportive criteria for the diagnosis of RLS [4]. In clinical practice, it is common that pramipexole is effective for RLS from the first days of treatment. These empirical data have never been demonstrated by an experimental procedure. The aim of the present investigation was to evaluate the initial response to a standard low dose of pramipexole, in a cohort of drug-naı¨ve patients affected by idiopathic RLS, by means of a controlled clinical PSG study.
10 during the baseline PSG (see below). Patients with an apnea/hypopnea index >5 were excluded. Results of neurological examination in all patients were unremarkable. Routine blood tests (including serum iron and ferritin, B12 vitamin, and folate), as well as electromyography (EMG) and electroneurography of the lower limbs, were also normal. Patients suffering from known causes of secondary RLS (e.g., renal failure, anemia with iron-deficiency, pregnancy, rheumatoid arthritis, or clinical peripheral neuropathy), other sleep disorders (e.g., narcolepsy, parasomnia and sleep breathing disorder), other movement disorders, or any medical conditions that would affect the assessment of RLS (e.g., fibromyalgia syndrome) were also excluded. Subjects were randomly assigned to two groups (treated and placebo) and underwent an adaptation night in the lab, followed by two nocturnal PSG recordings. No medication was administered before the first night recording (baseline). Before the second night of recording, subjects included in the treatment group received a single oral dose of 0.25 mg pramipexole at 9:00 p.m., while the remaining patients received placebo. All patients gave their written consent for these procedures and were unaware of the content (drug or placebo) of the medication. In the morning, after each PSG recording, all patients evaluated the severity of their previous night symptoms by means of the Visual Analogical Scale (VAS) [12]. The local ethical committee approved the study. 2.2. Nocturnal polysomnographic (PSG) studies
2. Subjects and methods 2.1. Subjects A prospective single-blind controlled study was carried out in consecutive subjects affected by idiopathic RLS. According to the International RLS Study Group, the minimal criteria for the diagnosis of RLS were leg restlessness, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs; beginning or worsening of this unpleasant sensation during rest or inactivity such as lying or sitting; partial or total relief of the unpleasant sensations by movement; and worsening or occurrence of the unpleasant sensations in the evening or night, compared to daytime [11]. To be included in the study, the mean frequency of symptoms during the last six months had to be greater than two times per week, with a score of at least 20 on the International RLS Study Group rating scale (corresponding to severe RLS) at the time of enrollment [11]. Only patients free of medication at the time of the evaluation, and never previously treated for RLS (dopaminergic agents, benzodiazepines, opioids and anticonvulsants), were included. Additional inclusion criteria were being between 18 and 70 years old and having a PLMS index greater than
Nocturnal PSGs were carried out after a night of adaptation in a standard sound-attenuated (noise level to a maximum of 30 dB nHL) sleep laboratory room. Subjects were not allowed to drink caffeinated beverages six hours before the beginning of each PSG and were allowed to sleep until their spontaneous awakening in the morning. Lights-out time was based on the individual’s usual bedtime and ranged between 10:30 and 11:30 p.m. The following signals were recorded: electroencephalogram (EEG) (six channels, including C3 or C4 and O1 or O2, referred to the controlateral mastoid); electrooculogram (EOG; electrodes placed 1 cm above the right outer cantus and 1 cm below the left outer cantus and referred to the mastoid); EMG of the submentalis muscle; EMG of the right and left tibialis anterior muscles (bipolar derivations with two electrodes placed 2 cm apart on the anterior tibialis muscle of each leg, impedance was kept less than 10 KX, according to the American Sleep Disorders Association (ASDA) scoring criteria) [13]; and electrocardiogram (ECG; one derivation). Sleep signals were sampled at 200 Hz and stored on hard disk in European data format (EDF) [14] for further analysis. EMG signals, in particular, were digitally band-pass filtered at 10–100 Hz, with a notch filter
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at 50 Hz. The sleep respiratory pattern of each patient was monitored using oral and nasal airflow thermistors and/or nasal pressure cannula, thoracic and abdominal respiratory effort strain gauge and by monitoring oxygen saturation (pulse-oximetry). This was performed in all subjects in a previous recording (within 1 week) or during the study recording. 2.3. Sleep scoring and detection of leg movements Prior to any recording, we verified that the EMG amplitude recorded from the two tibialis anterior muscles was below 2 lV at rest and exceeded 7–10 lV for small voluntary dorsiflexions of the foot. EMG amplitude at maximal deflection was also measured for the application of the ASDA scoring criteria [13]. Sleep stages were scored following standard criteria [15] on 30-s epochs using the sleep analysis software Hypnolab 1.2 (SWS Soft, Italy). Leg movements (LM) during sleep were first detected by the same software, which allows for computer-assisted detection. With this software, detection of LMs is performed using a human-supervised automatic approach controlled by the scorer following ASDA criteria [13]. The performance of this system has been recently evaluated and validated [16], but in this study one scorer visually edited, epoch by epoch, the detections proposed by the automatic analysis, before computing a final result. In particular, the total LM index was calculated to represent the total number of LM per hour of sleep. The PLMS index was calculated as the number of LM included in a series of four or more, separated by more than five and less than 90 s, per hour of sleep. Analysis included the PLMS index of the entire night, and separately of REM and NREM sleep, as well as the total number of LMs and number of PLMS sequences. Finally, the change in PLMS index observed between the baseline and the treatment nights was normalized for its baseline value by means of the calculation of the following ratio: ðbaseline PLMS index treatment PLMS indexÞ=baseline PLMS index that will be indicated here as ‘‘PLMS change index’’. Mathematically, this index can vary from +1 (complete disappearance of PLMS in the treatment night) to 1 (appearance of PLMS in the treatment night).
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2.4. Statistical analysis The comparison between the different sleep and LM parameters obtained before and after the administration of pramipexole or placebo was carried out by means of the factorial analysis of variance (ANOVA), with ‘‘group’’ (pramipexole or placebo) and ‘‘night’’ (baseline or treatment) as factors, which was followed by post hoc analysis for the individual group or night comparisons. For this analysis, the significance level was set at p < 0.05 and the commercially available Statistica software package (StatSoft, Inc., 2001. STATISTICA data analysis software system, version 6. www.statsoft.com) was used. 3. Results Thirty-two consecutive untreated patients were included in this study (mean age 58.4 ± 11.6, 9 males and 23 females); 18 patients received pramipexole and 14 were given placebo. Table 1 reports the demographic data of the patients and the results of the subjective evaluation of the severity of the RLS symptoms measured before treatment by the International RLS Study Group rating scale. One patient treated with pramipexole and another who was administered placebo reported mild morning nausea; no other significant side effects were reported by any of the rest of the patients. The mean VAS score before and after treatment changed from 7.4 ± 1.68 standard deviation (SD) to 1.3 ± 1.62 SD (p < 0.00001) in the pramipexole group, and from 6.8 ± 1.72 SD to 5.4 ± 2.33 SD (not significant) in the placebo group. The VAS score improved in all subjects and reached the value of 0 in 10 out of 18 patients treated with pramipexole, while it did not change in two patients and became worse in another three who took the placebo. Table 2 shows the comparison between the different sleep scoring parameters obtained before and after the administration of pramipexole or placebo. In this table, the ANOVA was significant only for the factor ‘‘night’’ and for the percentage of sleep stage 2 which was increased in the pramipexole treatment night. Other parameters, in addition, such as time in bed and sleep efficiency, tended to show evident modifications in the pramipexole treatment night but these differences did not reach statistical significance.
Table 1 Demographic data of the patients and results of the subjective evaluation of RLS symptom severity, measured before treatment by the International RLS Study Group rating scale
Total Pramipexole group Placebo group
Males (n)
Females (n)
Age, mean (SD)
IRLSSG score, mean (SD)
9 4 5
23 14 9
58.4 (11.6) 59.8 (11.2) 56.6 (12.3)
27.0 (4.85) 27.3 (5.19) 26.6 (4.55)
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Table 2 Comparison between the different sleep scoring parameters obtained before and after the administration of pramipexole or placebo 1st Night Pramipexole Mean SD TIB (min) 512.9 SPT (min) 473.4 TST (min) 343.5 SOL (min) 27.1 FRL (min) 134.4 SS/hour 11.0 AWN/hour 4.8 Sleep efficiency, % 65.6 WASO (min) 129.9 S1 (min) 26.1 S2 (min) 184.4 SWS (min) 66.2 REM (min) 66.8 WASO, % 29.7 S1(%) 5.5 S2 (%) 38.7 SWS (%) 13.1 REM (%) 13.1
100.02 102.64 131.20 34.98 79.45 4.23 2.95 21.00 78.27 24.01 66.79 41.04 41.38 19.73 5.02 10.50 7.64 7.69
2nd Night Placebo
Pramipexole
ANOVA Placebo
Post hoc Baseline vs. Treatment Pramipexole vs. Placebo
Mean SD
Mean SD
Mean SD
Night Group Pramipexole Placebo Baseline Treatment
509.3 473.3 378.4 22.7 100.5 12.3 4.6 74.3 94.9 30.5 199.8 69.7 78.5 19.8 6.3 41.9 15.4 16.5
525.6 499.9 414.3 12.4 140.8 14.2 5.7 78.9 85.6 33.3 253.6 66.2 61.3 17.2 6.6 50.6 13.5 12.2
481.6 453.3 354.1 17.3 122.2 12.4 4.6 74.3 99.2 24.8 191.9 74.0 63.4 21.0 5.5 43.4 16.3 13.8
NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS 0.02 NS NS
89.97 87.87 87.60 24.06 40.93 3.35 2.44 10.02 61.31 19.71 66.71 37.66 29.39 11.99 3.72 10.70 9.70 5.23
44.87 45.76 57.86 8.14 99.15 4.48 3.71 8.36 40.16 26.47 66.01 35.99 28.48 7.99 4.93 12.13 7.84 5.18
97.79 93.72 76.44 21.93 67.81 4.16 2.33 11.07 71.27 22.74 46.61 31.60 21.46 12.05 4.64 10.85 6.46 3.98
NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS
0.0005
NS
TIB, time in bed; SPT, sleep period time; TST, total sleep time; SOL, sleep onset latency; FRL, first REM latency; SS, stage shifts; AWN, awakenings number; WASO, wakefulness after sleep onset;S1, stage 1; S2, stage 2; SWS, slow-wave sleep; REM, REM sleep.
Table 3 reports the comparison between the different LM scoring parameters obtained before and after the administration of pramipexole or placebo. In this comparison, whole-night PLMS index and NREM sleep total LM and PLMS index were significantly lower during the pramipexole treatment night than during the baseline recording. The same parameters showed a statistically significant difference between the two patient groups, after treatment but not at baseline. No detectable changes followed the placebo treatment. Fig. 1 shows, for example, the hypnogram of the baseline and treatment nights in a patient who was administered pramipexole; in this figure it is possible to see the important changes in LM activity (a detail is shown in the upper panel, in baseline conditions) and of sleep structure occurring after treatment. Fig. 2 reports the individual and average (with SD) values of the PLMS change index in the two groups of patients; it is possible to notice that the pramipexole group shows significantly higher values of this index than the placebo group (p < 0.00001). Moreover, 13 out of 18 subjects receiving pramipexole show a PLMS change index higher than the highest observed in the placebo group (0.726); the same figure also shows the individual values of the PLMS index in both groups of patients, at baseline and after treatment. Finally, no significant correlation was found between the PLMS change index and the magnitude of VAS change for subjects receiving pramipexole (Pearson r = 0.140) or placebo (Pearson r = 0.106).
4. Discussion The acute administration of a low dose (0.25 mg) of pramipexole in treatment-naı¨ve, idiopathic, severe RLS patients markedly improved the symptoms from the first night of therapy in all treated subjects, leading to a complete disappearance of symptoms in more than half of the cases. The most remarkable objective effect of pramipexole is represented by the immediate drop of the PLMS index, clearly evident in all subjects who took the drug. Despite the inclusion of severe RLS patients with PLMS, our unambiguous results may be also an effect of the fact that only patients who had never been treated for RLS previously were included. At the same time it is important to note that, as expected because of their occurrence during sleep, PLMS do not seem to be influenced by the placebo effect [11]. The abrupt response of symptoms and PLMS to pramipexole stands for a possible common dopaminergic origin of both of these pathological phenomena [17]. Our results support the hypothesis of a direct involvement of D3 subtype receptors in the pathogenesis of PLMS and RLS symptoms [18–20]. Pramipexole is a potent dopamine auto-receptor agonist which interacts with dopamine G protein-coupled D2 subfamily receptors (D2, D3, and D4 subtypes) showing a weaker bind to D1 subfamily receptors (D1 and D5 subtypes) and almost absent to adrenergic or serotonergic receptors [21]. Furthermore, pramipexole has a preferential affinity to D3 receptors with a selectivity 15 times more potent at D3 than D2
0.0003 0.0002
0.00007 0.00005
NS NS
NS NS
NS NS
NS NS
0.014 0.013 NS 0.036 NS 37.69 36.79 4.44 58.4 48.8 10.5 12.25 11.40 7.79 19.3 9.4 7.1 25.03 25.73 5.86 51.1 42.3 11.9 54.3 45.8 11.4 Total Total LM index PLMS index PLMS Sequence number
34.61 33.56 4.89
35.6 24.3 REM sleep Total LM index PLMS index
40.55 43.72
27.1 15.9
17.60 17.11
17.4 3.8
8.89 4.66
32.0 21.4
27.61 31.62
NS NS
NS NS
0.0002
0.0003 0.00007 0.004 0.004 0.037 0.021 39.21 37.94 64.2 55.0 14.15 13.12 19.6 10.4 27.94 28.63 57.4 49.2 34.47 32.84 58.1 50.4
Night SD Mean SD SD
SD
Mean Mean Mean
NREM sleep Total LM index PLMS index
Tretament Baseline Placebo Pramipexole Group
Post hoc
Baseline vs. Treatment
ANOVA Pramipexole
Placebo 2nd Night
Pramipexole Placebo
1st Night
Table 3 Comparison between the different scoring parameters for leg movements, obtained before and after the administration of pramipexole or placebo
Pramipexole vs. Placebo
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receptors [22]. D3 receptors appear to be concentrated in the limbic system, which is more related to cognitive aspects, and in the dorsal horns and intermediolateralgray matter of the spinal cord, likely to be involved in nociceptive modulation [23–26]. Spinal D3 receptors receive dopaminergic projections from the A11 nuclei, located within the lateral hypothalamus, which are suspected to play a role in the pathogenesis of RLS, and are closely related to the central circadian pacemaker of the suprachiasmatic nucleus [27]. In comparison to the effect on the subjective RLS components and on PLMS, the pharmacological effect on sleep macrostructure is less clear-cut but leans toward being a general improvement of hypnic parameters. From a panoramic vision of the PSG results, a tendency towards a quantitative sleep improvement (sleep effiency, total sleep time), especially for the light NREM stages, after acute pramipexole treatment, becomes evident. Part of these results did not reach statistical significance probably because of the high variance of the data. Interestingly, this rise in sleep quantity does not seem to be accompanied by a similar improvement in sleep continuity, with a propensity toward sleep fragmentation (increased number of awakenings/hour and stage shifts/hour) and an inefficacy in consolidating slow wave sleep. Probably, a longer period of treatment would be necessary for a more effective stabilization of sleep continuity. Moreover, PLMS might not be directly responsible for the instability in EEG microstructure and the disappearance of LMs is not automatically followed by a similar reduction in sleep fragmentation indexes. Saletu et al. [10] performed an acute (night-to-night) treatment evaluation in RLS patients by using 0.5 mg of ropinirole and found a significant ‘‘decrease in arousals due to PLMS, but an increase in spontaneous arousals after medication’’. This effect may also be interpreted as a selective action of ropinirole on PLMS, without a direct influence on the electro-cortical arousal activity that remains unchanged after treatment. The demonstration of an immediate efficacy of ropinirole and pramipexole is extremely important, not only because it is an obvious benefit to patients able to obtain rapid therapeutic results, but also because it opens the doors to two other possibly crucial drug applications, already discussed, in the near future for idiopathic RLS: on-demand therapy and the use of a standard single dopaminergic agent as a diagnostic ex-juvantibus test [28,29]. On-demand therapy may have significant results for patients with moderate or intermittent symptoms and for patients (treated and untreated) who are going to face forced immobility for a long time, such as in air, train or car travel, social events during the evening or sedentary working postures. In these cases, it is recommended that patients take the drug about 40– 60 min before the onset of the desired therapeutic window and choose middle/short half-life dopamine-agonists
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Fig. 1. Examples of the hypnogram at baseline and treatment nights (bottom panels) in a patient who was administered pramipexole; a short PSG segment of the baseline recording is shown in the top panel, for example. Abbreviations: LOC, ROC, left and right electro-oculogram; A1, A2, left and right earlobes; ECG, electrocardiogram; W, wakefulness; R, REM sleep; S1, S2, S3, S4, sleep stages 1, 2, 3, and 4.
Fig. 2. Individual and average (with S.D., whiskers) values of the PLMS change index in the two groups of patients (middle panel); individual values of the PLMS index in patients treated with pramipexole (left panel) and in those treated with placebo (right panel), at baseline and after treatment.
that do not need a pre-medication [28]. Regarding the second possible application, notwithstanding the fact that all of our patients showed an improvement in PLMS and symptoms (high sensitivity), the diagnostic value of a single-shot drug test might be decreased by the existence of false responders (low specificity), similarly to patients who show improved PLMS index or symptoms as a result of physiological night-to-night variability. We must also note that a possible limit of our
study was the absence of a longer period of baseline evaluation. On the other hand, a diagnostic test might be useful even if it can only exclude the diagnosis of RLS in the case of worsening of PLMS and/or symptoms; in fact, we never observed in our study an increase in PLMS index in subjects treated with pramipexole. The real feasibility of this hypothetical test should be also evaluated on the basis of cost, because the patients need to undergo two consecutive full-night PSG studies;
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however, this might be acceptable in consideration of long-term therapy needed in RLS. Moreover, the repeated application of the Suggested Immobilization Test instead of the full-night PSG could reduce diagnostic costs and time of execution [30]. In conclusion, our investigation demonstrates the immediate effectiveness and the excellent tolerability of a low standard dose of pramipexole in RLS patients, suggesting interesting pathogenetic speculations and important consequences on clinical practice for a possible on-demand treatment. The use of pramipexole in a diagnostic test needs further evidence in terms of reliability and suitability. References [1] Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003;4:101–19. [2] Walters AS. Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov Disord 1995;10:634–42. [3] Thorpy MJ. New paradigms in the treatment of restless legs syndrome. Neurology 2005;64:S28–33. [4] Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep 1996;19:205–13. [5] Walters AS, Hening WA, Kavey N, Chokroverty S, Gidro-Frank S. A double-blind randomized crossover trial of bromocriptine and placebo in restless legs syndrome. Ann Neurol 1988;24:455–8. [6] Ondo W, Romanyshyn J, Vuong KD, Lai D. Long-term treatment of restless legs syndrome with dopamine agonists. Arch Neurol 2004;61:1393–7. [7] Allen R, Becker PM, Bogan R, Schmidt M, Kushida CA, Fry JM, et al. Ropinirole decreases periodic leg movements and improves sleep parameters in patients with restless legs syndrome. Sleep 2004;27:907–14. [8] Manconi M, Casetta I, Govoni V, Cesnik E, Ferini-Strambi L, Granieri E. Pramipexole in Restless Legs syndrome. Evaluation by suggested immobilization test. J Neurol 2003;250:1494–5. [9] Saletu M, Anderer P, Saletu B, Hauer C, Mandl M, Oberndorfer S, et al. Sleep laboratory studies in restless legs syndrome patients as compared with normals and acute effects of ropinirole. 2. Findings on periodic leg movements, arousals and respiratory variables. Neuropsychobiology 2000;41:190–9. [10] Saletu M, Anderer P, Saletu-Zyhlarz G, Hauer C, Saletu B. Acute placebo-controlled sleep laboratory studies and clinical follow-up with pramipexole in restless legs syndrome. Eur Arch Psychiatry Clin Neurosci 2002;252:185–94. [11] Walters AS, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2003;4:121–32.
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