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Proposed dose equivalence between clonazepam and pramipexole in patients with restless legs syndrome
Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) 522–526
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Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p
Proposed dose equivalence between clonazepam and pramipexole in patients with restless legs syndrome Hideto Shinno a,⁎, Yasunori Oka b, Manabu Otsuki c, Satoshi Tsuchiya d, Soichi Mizuno e, Seiichi Kawada f, Toshihiko Innami g, Akira Sasaki h, Takashi Hineno i, Tetsuro Sakamoto j, Yasushi Inami k, Yu Nakamura a, Jun Horiguchi l a
Department of Neuropsychiatry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kida, Kagawa 761-0793, Japan Department of Sleep Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan c Otsuki Sleep Clinic, 4-16 Wase, Fukushima, Fukushima 960-8044, Japan d Tsuchiya Clinic, 2-3-11 Uemachi, Ube, Yamaguchi 755-0051, Japan e Department of Psychiatry, Fukuyama Medical Center, 14-17 Okinogamicho, Fukuyama, Hiroshima 720-8520, Japan f Kochi Kagamigawa Hospital, 270 Joyama, Kochi, Kochi 780-8037, Japan g Innami Ophthalmology and Neurology Clinic, 380-1 Taguchi, Ohzu, Ehime 795-0063, Japan h Saijo Dozen Hospital, 3290-1 Iiokajizouhara, Saijo, Ehime 793-0010, Japan i Hineno Clinic, 4-5-1 Umagoe, Imabari, Ehime 794-0062, Japan j Yuai Hospital, 728-1 Nakashou, Higashi-miyoshi, Miyoshi, Tokushima 779-4703, Japan k Department of Psychiatry, Ehime Rosai Hospital, 13-27 Minami-komatsubara, Niihama, Ehime 792-8550, Japan l Department of Psychiatry, Shimane University Faculty of Medicine, 89-1 Enya, Izumo, Shimane 693-8501, Japan b
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Article history: Received 25 December 2009 Received in revised form 12 January 2010 Accepted 9 February 2010 Available online 13 February 2010 Keywords: Clinical Global Impressions — Severity of illness (CGI-S) Clonazepam Equivalent ratio Pramipexole Restless legs syndrome (RLS) The International Restless Legs Syndrome Study Group rating scale (IRLS)
a b s t r a c t Background: Dopamine agonists are accepted as the first-line medications for restless legs syndrome (RLS). In some Asian countries, clonazepam is one of the prevalent medications for RLS because of its effect on sleep disturbances. To date, there have not been any studies that examined equivalent doses of pramipexole and clonazepam. To evaluate equivalent doses of pramipexole and clonazepam in RLS, we investigated the efficacy and tolerability after conversion from clonazepam to pramipexole, and examined dose equivalence between the two prescriptions. Methods: In a prospective, open-label, multicenter study, 26 RLS patients treated with clonazepam (mean age: 69.2 ± 11.0 years old) were enrolled and then rapidly switched to pramipexole using a conversion calculation of 4:1 for daily doses. Then the daily dose of pramipexole was up titrated or tapered by 0.125 mg/ day at each subsequent examination. RLS symptoms and daytime somnolence were evaluated using the International RLS Study Group rating scale (IRLS), Clinical Global Impressions — Severity of illness (CGI-S) and the Epworth Sleepiness Scale (ESS), respectively. Results: Conversion from clonazepam to pramipexole resulted in significant reductions of IRLS (16.3 ± 8.7 to 9.1 ± 6.3) and ESS (6.5 ± 4.2 to 4.4 ± 3.2). CGI scores demonstrated improvement after conversion. In 4 patients (15%), adverse events such as somnolence, sensation of oppression in the lower limbs, diarrhea, or nausea were present. Correlation analysis demonstrated a significant relationship between these daily doses. Spearman's correlation coefficient was 0.662. Our study, however, has some limitations since it is an openlabel trial and includes only 26 patients. Further studies using a double-blind design or a crossover design are recommended. Conclusions: Statistical analysis demonstrated a 4:1 conversion for clonazepam to pramipexole. When switchover from clonazepam to pramipexole is done, this conversion ratio may be helpful to determine the initial dose of pramipexole for treating RLS. © 2010 Elsevier Inc. All rights reserved.
Abbreviations: CGI-S, Clinical Global Impression of Severity; ESS, Epworth Sleepiness Scale; IRLS, International Restless Legs Syndrome Rating Scale; MDS, Movement Disorder Society; PLM, periodic limb movements; RLS, restless legs syndrome. ⁎ Corresponding author. Department of Neuropsychiatry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793, Japan. Tel.: + 81 87 891 2165; fax: + 81 87 891 2168. E-mail address: [email protected] (H. Shinno). 0278-5846/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2010.02.011
1. Introduction Restless legs syndrome (RLS) is a neurological disorder characterized by an urge to move, and usually associated with uncomfortable leg sensations (Montplaisir et al., 2005). The National Institutes of Health RLS workshop (Allen et al., 2003) has defined the diagnostic
H. Shinno et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) 522–526
criteria. The four essential criteria are: (1) an urge to move, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs; (2) the urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying and sitting; (3) the urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as activity continues; and (4) the urge to move or unpleasant sensations are worse in the evening or night than during the day or occur only in the evening or night. Most RLS patients report difficulties falling asleep (Montplaisir et al., 2005). It is also difficult for patients with RLS to maintain their sleep because they awaken with unpleasant sensations shortly after sleep onset (Montplaisir et al., 2005). As a consequence of frequent arousals from nocturnal sleep, patients often experience excessive daytime fatigue and somnolence. It is, therefore, mandatory to treat RLS adequately. Dopaminergic medications are now widely prescribed for RLS treatment. Initially, the short-term efficacy of L-dopa was well documented. Polysomnographic studies showed that L-dopa administration induced a significant reduction in RLS symptoms present at bedtime as well as reducing periodic limb movements (PLM) throughout the night (Brodeur et al., 1988). Varying degrees of longterm benefit from L-dopa, however, have been found, ranging from 85% (von Scheele and Kempi, 1990) to 31% (Earley and Allen, 1996) after a few years. Several adverse effects have been reported in patients treated with L-dopa, such as nausea, vomiting, tachycardia, orthostatic hypotension, hallucinations, and insomnia. Morning rebound and RLS augmentation are known as more specific adverse effects. Dopaminergic agonists are now considered the first-line treatment for RLS because they are more effective and produce fewer adverse effects. In this decade, pramipexole, non-ergoline derivative agonists for dopamine D2/D3 receptor, have been studied for RLS treatment (Montplaisir et al., 1999). Results from several double-blind, placebo-controlled studies have demonstrated the superiority of pramipexole for the broad range of RLS symptoms (Ferini-Strambi et al., 2008; Oertel et al., 2007; Winkelman et al., 2006). There have also been several long-term studies demonstrating sustained efficacy of pramipexole in RLS (Silber et al., 2003; Winkelman and Johnston, 2004). Several studies have shown that benzodiazepines such as clonazepam improve the quality of sleep and reduce periodic limb movements during sleep (PLMs) as well as PLMs-associated arousals in patients with RLS, as has been reported its acute therapeutic efficacy regarding insomnia (Saletu et al., 2001). Clonazepam is prescribed to improve sleep continuity and used as an adjunct treatment because dopaminergic agents sometimes worsen insomnia. However, regarding subjective RLS symptoms, sufficient studies demonstrating the effects of clonazepam have not been conducted (Trenkwalder et al., 2008), even though clonazepam prescription is prevalent in some countries of Asia and Europe. To date, there have not been any studies on the conversion to nonergot dopamine agonists in patients with RLS, although several articles have reported the conversion from ergot to non-ergot dopamine agonists in patients with advanced Parkinson's disease (Goetz et al., 1999; Hanna et al., 2001). Furthermore, there have not been any studies examining equivalent doses of pramipexole and clonazepam. The aim of this study is to evaluate equivalent doses of pramipexole and clonazepam in Japanese patients with RLS, using efficacy and tolerability after switching from clonazepam to pramipexole as indications of dose equivalence.
2. Methods 2.1. Study design The study was conducted at 11 centers in Japan. This study was a prospective, open-label study design to assess the therapeutic equiva-
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lence of progressive switching from clonazepam to pramipexole. Data were collected between September 2008 and September 2009. 2.2. Patients Twenty-six patients with idiopathic and secondary RLS were enrolled in this study. The diagnosis of RLS was made according to the essential criteria established by the International RLS Study Group (Allen et al., 2003). All patients were treated with therapeutic levels of clonazepam monotherapy, and required a switch for one or more of the following reasons: i) inability to achieve satisfactory symptom control due to doselimiting side effects experienced with clonazepam; ii) inability to adequately tolerate clonazepam monotherapy even in the presence of acceptable symptom control; iii) patients who, despite achieving adequate symptom control, were prone to recurrent clinical conditions requiring treatment with drugs known to interact with clonazepam. Patients were eligible if (i) they were aged ≥20 years, (ii) clonazepam had been prescribed (≤2.0 mg/day), (iii) daily doses of clonazepam did not change for more than 4 weeks, and no other drugs were prescribed for RLS. Patients were excluded for pregnancy or breast-feeding; for having contraindications to pramipexole; for comorbidity with other sleep disorders. Patients were also excluded from this study if the causes of RLS were pregnancy, renal failure, artificial dialysis, or drugs such as neuroleptics and antidepressants. The local institutional research boards approved this study. All patients gave informed consent according to institutional guidelines and the tenets of the Declaration of Helsinki. 2.3. Treatment If patients had been prescribed less than 1 mg/day of clonazepam, clonazepam was discontinued and pramipexole was prescribed. The initial daily dose of pramipexole was calculated using a conversion of 1:4 for clonazepam dose (Fig. 1A). However, if the patients had been prescribed 1 mg/day or over 1 mg/day of clonazepam, two protocols for switching were adopted (Fig. 1B). One protocol was the rapid switch, which was the same as for patients pretreated with a lower dose of clonazepam (Fig. 1B-(a)). The other was gradual switching. Intermediate doses of clonazepam and pramipexole were prescribed for a week followed by a complete switch to pramipexole (Fig. 1B-(b)). As RLS symptoms and adverse effects were observed, the dose of pramipexole was titrated. The daily dose of pramipexole was up titrated or tapered by 0.125 mg/day at each subsequent examination. 2.4. Measurements We evaluated the severity of RLS symptoms using the International Restless Legs Syndrome Rating Scale (IRLS) (The International Restless Legs Syndrome Study Group, 2003). Daytime somnolence was measured by the Epworth Sleepiness Scale (ESS) (Johns, 1991). We objectively evaluated severity using the Clinical Global Impression of Severity (CGI-S). We assessed the International RLS Study Group rating scale (IRLS), ESS, and CGI-S at each examination. Adverse events were also elicited at each examination. 2.5. Data analysis To assess changes in scores on the IRLS, the ESS, and CGI-S, we used a Wilcoxon's signed-rank test. According to the severity of RLS symptoms, patients were divided into four categories: none or mild (IRLS score 0–10), moderate (IRLS score 11–20), severe (IRLS score 21–30), and very severe (IRLS score 31–40). The distribution of patients across severity categories was compared before and after switching using the chi-square test. The relationship between the daily doses of clonazepam and those of pramipexole after conversion was analyzed using Spearman's correlation.
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Fig. 1. Mode of conversion from clonazepam to pramipexole. (Panel A) If patients had been prescribed less than 1 mg/day of clonazepam, clonazepam was discontinued and pramipexole was prescribed. The initial daily dose of pramipexole was calculated using a conversion of 1:4 for the clonazepam dose. (Panel B) If the patients had been prescribed 1 mg/day or over 1 mg/day of clonazepam, two protocols for switching were adopted. One protocol was the rapid switch, which was the same as adopted for patients pretreated with a lower dose of clonazepam (as shown in B-(a)). The other protocol was gradual switching. Intermediate doses of clonazepam and pramipexole were prescribed for a week followed by a complete switch to pramipexole (as shown in B-(b)).
15.4± 9.0 and 6.5 ± 4.2, respectively. The mean daily dose of clonazepam was 0.82 ± 0.31 (0.5–1.5 mg/day).
3. Results 3.1. The demography and baseline characteristics of subjects (Table 1) Twenty-six patients were enrolled in this study (14 males and 12 females). Twenty-three patients had primary RLS and three patients had secondary RLS. The mean age was 69.2 ± 11.0 years old (44 to 86 years old). The mean duration of RLS was 65.0 ± 72.8 months. The mean IRLS score and ESS score before pramipexole prescription were Table 1 The demography and baseline characteristics of the subjects. Gender, n (%) Male 14 (53.8%) Female 12 (46.2%) Mean age (years old) 69.2 ± 11.0 [44–86] Age, n (%) b65 y.o. 7 (26.9%) ≥65 y.o. 19 (73.1%) Duration of RLS (months) 65.0 ± 72.8 [2–244] Mean total IRLS score 15.4 ± 9.0 [0–33] Mean CGI-S score 3.8 ± 1.2 [1–6]
Mean ESS score 6.5 ± 4.2 [0–17] Severity of RLS symptoms, n (%) Mild 8 (30.8%) Moderate 9 (34.6%) Severe 8 (30.8%) Very severe 1 (3.8%)
3.2. The RLS symptoms Of the 26 subjects, 24 patients completed this study. The severity of RLS symptoms before and after conversion was compared in these 24 patients. The mean IRLS score was 16.3 ± 8.7 before conversion. After conversion to pramipexole was accomplished, the mean IRLS score was 9.1 ± 6.3, which was a significant decrease (p = 0.002) (Fig. 2). When the distribution of severity categories (none or mild, moderate, severe, and very severe) before switching was compared with that after conversion to pramipexole, we found a significant difference between the two periods (p = 0.016) (Table 2).
Classification of RLS, n (%) Primary 23 (88.5%) Secondary 3 (11.5%) Daily dose of clonazepam (mg/day) Mean 0.82 ± 0.31 [0.5–1.5] Daily dose of clonazepam, n (%) 0.5 mg/day 11 (36%) 0.75 mg/day 1 (5%) 1.0 mg/day 12 (50%) 1.5 mg/day 2 (9%)
Values represent the mean with standard deviation. Range is shown in a bracket parenthesis.
Fig. 2. Effect of pramipexole on the RLS symptoms. RLS symptoms were evaluated using International Restless Legs Syndrome Study Group rating scale (IRLS) [16]. The IRLS scores before the switch and those after the switch to pramipexole were compared. Data were analyzed by Wilcoxon's signed-rank test. **p b 0.01.
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Table 2 Comparison of severity category. Severity categories of RLS symptoms None or mild
Before switch After switch
Moderate
Severe
Very severe
IRLS score
IRLS score
IRLS score
IRLS score
0–10
11–20
21–30
31–40
6 (25.0%) 16 (66.7%)
9 (37.5%) 7 (29.2%)
8 (33.3%) 1 (4.2%)
1 (4.2%) 0 (0%)
The severity of restless legs syndrome (RLS) symptoms was evaluated with the International Restless Legs Syndrome Rating Scale (IRLS) [16]. Patients were divided into 4 categories based on symptom severity. The categories were defined as “none or mild” (IRLS score 0–10), “moderate” (IRLS score 11–20), “severe” (IRLS score 21–30), and “very severe” (IRLS score 31–40). The distributions of severity categories before and after the switch to pramipexole were compared using the chi-square test. *p b 0.05.
Fig. 4. Global Impression of the severity of illness. Global impression of the severity of illness was evaluated using Clinical Global Impression — Severity of illness (CGI-S). The CGI-S scores before the switch and those after the switch to pramipexole were compared. Data were analyzed by Wilcoxon's signed-rank test. **p b 0.01.
3.3. The daytime somnolence
4. Discussion
The mean ESS score was 6.5 ± 4.4 before conversion. After conversion to pramipexole was accomplished, the mean ESS score was 4.4 ± 3.2, which was a significant decrease (p = 0.004) (Fig. 3).
Restless legs syndrome is relatively common, with a prevalence ranging from 2.5% to 10% in the general population (Allen et al., 2005; Rothdach et al., 2000). Although the pathophysiology of RLS is not yet sufficiently understood, evidence has shown that a dopaminergic pathway may be involved (Allen, 2004; Trenkwalder and Paulus, 2004). The Movement Disorder Society (MDS) commissioned a task force to perform an evidence-based review of current treatment strategies, and non-ergot-derived dopamine agonists were indicated to be efficacious treatment for RLS [13]. Pramipexole, a non-ergoline dopamine agonist, was shown to be successful in the treatment of RLS in double-blind, placebo-controlled, crossover, randomized studies enrolling large numbers of subjects (Ferini-Strambi, et al. 2008; Montplaisir et al., 1999; Oertel et al., 2007; Partinen et al., 2006; Trenkwalder et al., 2006; Winkelman et al., 2006). Periodic limb movements during sleep (PLMs) is most often associated with RLS, while a frequent comorbidity with other sleep disorders, such as sleep apnea, narcolepsy, parasomnia, has also been reported (Boehm et al., 2009; Hornyak et al., 2006). Disturbances with a significant impact on the quality of life as well as increased PLM indices (number of PLM per hour of time in bed) are common in RLS (Boehm et al., 2009). Some studies have reported that clonazepam is prescribed to improve sleep continuity in patients with RLS (Boghen et al., 1986; Matthews, 1979; Montagna et al., 1984; Read et al., 1981) because dopaminergic agents sometimes worsen insomnia. There is,
3.4. The adverse events We observed the physical condition and examined adverse events at every visit. Of the 4 patients who exhibited adverse events, two patients required the discontinuation of pramipexole due to mild nausea (daily dose of pramipexole: 0.25 mg/day) or diarrhea (daily dose of pramipexole: 0.25 mg/day), which lasted for 1 day and 3 days, respectively. The others transiently complained of somnolence (daily dose of pramipexole: 0.25 mg/day) and sensation of oppression in the legs (daily dose of pramipexole: 0.125 mg/day), but continued pramipexole treatment.
3.5. The objective impressions of severity The mean CGI-S scores at baseline and after conversion were 3.9 ± 1.3 and 2.7 ± 0.9, respectively (Fig. 4). Wilcoxon's signed-rank test demonstrated a significant decrease in CGI-S score (p = 0.004).
3.6. The equivalent ratio between clonazepam and pramipexole The relationship between daily doses of clonazepam and those of pramipexole was investigated (Table 3). Correlation analysis demonstrated a significant relationship between these daily doses. Spearman's correlation coefficient was 0.662 (p b 0.001). Using 4:1 as the equivalent dose ratio of clonazepam to pramipexole was valid.
Fig. 3. Comparison of daytime somnolence. Daytime somnolence was evaluated using Epworth Sleepiness Scale (ESS) [17]. The ESS scores before the switch and those after the switch to pramipexole were compared. Data were analyzed by Wilcoxon's signedrank test. **p b 0.01.
Table 3 The equivalent ratio between clonazepam and pramipexole.
The relationship between daily doses of clonazepam and those of pramipexole was investigated. Correlation analysis was carried out using Spearman's test. Spearman's correlation coefficient was 0.662 (p b 0.001). Shaded cells indicate the daily dose ratio of clonazepam 4 to pramipexole 1.
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however, no clear evidence that subjective or objective PLM measures of therapeutic benefit have been achieved. These studies did not measure or discuss daytime somnolence, although clonazepam has a very prolonged effect and may cause such somnolence. Although dopamine agonists such as pramipexole may cause daytime sleepiness, previous studies in patients with RLS demonstrated that there was no significant difference in ESS score between pramipexole and placebo (Partinen et al., 2006; Winkelman et al., 2006; Trenkwalder et al., 2006). As indicated in an evidence-based review established by the MDS-commissioned task force (Trenkwalder et al., 2008), the therapeutic effect of clonazepam on RLS may be investigational, although patients with subjective and/or objective sleep disturbances may indeed require treatment such as clonazepam. The strategy for conversion from clonazepam to dopaminergic agents should, therefore, be considered, when clonazepam fails to improve RLS symptoms sufficiently, or induces adverse effects. It remains controversial whether rapid switch is preferable to slow titration. There have been several studies on switching protocol in patients with Parkinson's disease (Goetz et al., 1999; Hanna et al., 2001), although switching protocol has not been investigated in patients with RLS. Reports have shown that rapid conversion was safer, and that some patients with slow titration experienced enhanced parkinsonism (Goetz et al., 1999). Based on these findings, we rapidly switched to pramipexole in principle and pramipexole dose was calculated using a daily milligram conversion of 1:4 for clonazepam dose. However, in patients pretreated with higher doses of clonazepam (over 1 mg/day), half daily doses of clonazepam were administered for a week instead of rapid discontinuation because it was necessary to prevent withdrawal symptoms. In the present study, a smaller proportion of subjects (4 of 26: 15.4%) exhibited adverse events. We consider that conversion to pramipexole may be relatively safe, although the lower percentage of adverse effects may be due to the lower daily doses of pramipexole prescribed for patients with RLS. To our knowledge, there have not been any studies that investigated the switchover from clonazepam to pramipexole in patients with RLS. The present study demonstrates the important and practical findings that had not been investigated in patients with RLS. First, the comparison of efficacy and safety between pramipexole and clonazepam seems to be meaningful because there have been no comparative trials to agents other than placebo. We have demonstrated that conversion to pramipexole resulted in improvements of RLS symptoms and daytime somnolence. We consider that pramipexole may be preferable to clonazepam. Second, we have defined a conversion ratio to facilitate switching from clonazepam to pramipexole in a simple, safe, and effective manner for patients with RLS. Statistical analysis confirmed that a 4:1 conversion ratio for clonazepam to pramipexole is appropriate. Our study, however, has some limitations since it is an open-label trial and includes only 26 patients. Further studies using a double-blind design or a crossover design are recommended. 5. Conclusion Conversion to pramipexole was demonstrated to be effective for RLS symptoms and daytime somnolence, and to be well tolerated. When switchover from clonazepam to pramipexole is required, a 4:1 conversion ratio for clonazepam to pramipexole may be helpful to determine the initial dose of pramipexole for treating RLS. Acknowledgements We certify that there was no financial support for this study. The authors are grateful to Dr. Tatsuru Horikoshi (Horikoshi Shinshin Clinic, Fukushima, Japan) and Dr. Hidehisa Yamashita (Hiroshima University Graduate School of Medicine, Hiroshima, Japan) for their useful suggestions.
References Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med 2004;5(4):385–91. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisir 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. 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(11):1286–92. Boehm G, Wetter TC, Trenkwalder C. Periodic leg movements in RLS patients as compared to controls: are there differences beyond the PLM index. Sleep Med 2009;10:566–71. Boghen D, Lamothe L, Elie R, Godbout R, Montplaisir J. The treatment of the restless legs syndrome with clonazepam: a prospective controlled study. Can J Neurol Sci 1986;13(3):245–7. Brodeur C, Montplaisir J, Godbout R, Marinier R. Treatment of restless legs syndrome and periodic limb movements during sleep with L-dopa: a double-blind, controlled study. Neurology 1988;38:1845–8. Earley CJ, Allen RP. Pergolide and carbidopa/levodopa treatment of the restless legs syndrome and periodic leg movements in sleep in a consecutive series of patients. Sleep 1996;19(10):801–10. Ferini-Strambi L, Aarskog D, Partinen M, Chaudhuri KR, Sohr M, Verri D, et al. Effect of pramipexole on RLS symptoms and sleep: a randomized, double-blind, placebocontrolled trial. Sleep Med 2008;9(8):874–81. Goetz CG, Blasucci L, Stebbins GT. Switching dopamine agonists in advanced Parkinson's disease. Neurology 1999;52(6):1227–9. Hanna PA, Ratkos L, Ondo WG, Jankovic J. Switching from Pergolide to pramipexole in patients with Parkinson's disease. J Neural Transm 2001;108(1):63–70. Hornyak M, Feige B, Riemann D, Voderholzer U. Periodic leg movements in sleep and periodic limb movement disorder: prevalence, clinical significance and treatment. Sleep Med Rev 2006;10:169–77. Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991;14(6):540–5. Matthews WB. Treatment of the restless legs syndrome with clonazepam. Br Med J 1979;1(6165):751. Montagna P, de Bianchi LS, Zucconi M, Cirignotta F, Lugaresi E. Clonazepam and vibration in restless legs syndrome. Acta Neurol Scand 1984;69(6):428–30. Montplaisir J, Nicolas A, Denesle R, Gomez-Mancilla B. Restless legs syndrome improved by pramipexole: a double-blind randomized trial. Neurology 1999;52(5):938–43. Montplaisir J, Allen RP, Walters AS, Ferini-Strambi L. Restless legs syndrome and periodic limb movements during sleep. In: Kryger M, Roth T, Dement W, editors. Principles and practice of sleep medicine. 4th edition. Philadelphia: Elsevier Saunders; 2005. p. 839–52. Oertel WH, Stiasny-Kolster K, Bergtholdt B, Hallström Y, Albo J, Leissner L, et al. The Pramipexole RLS Study Group. Efficacy of pramipexole in restless legs syndrome: a six-week, multicenter, randomized, double-blind study. Mov Disord 2007;22(2): 213–9. Partinen M, Hirvonen K, Jama L, Alakuijala A, Hublin C, Tamminen I, et al. Efficacy and safety of pramipexole in idiopathic restless legs syndrome: a polysomnographic dose-finding study — the PRELUDE study. Sleep Med 2006;7:407–17. Read DJ, Feest TG, Nassim MA. Clonazepam: effective treatment for restless legs syndrome in uremia. Br Med J 1981;283(6296):885–6. Rothdach AJ, Trenkwalder C, Haberstock J, Keil U, Berger K. Prevalence and risk factors of RLS in an elderly population: the MEMO study. Memory and Morbidity in Augsburg Elderly. Neurology 2000;54(5):1064–8. Saletu M, Anderer P, Saletu-Zyhlarz G, Prause W, Semler B, Zoghlami A, et al. Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD): acute placebocontrolled sleep laboratory studies with clonazepam. Eur Neuropsychopharmacol 2001;11(2):153–61. Silber MH, Girish M, Izurieta R. Pramipexole in the management of restless legs syndrome. Sleep 2003;26(7):819–21. The International Restless Legs Syndrome Study Group. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2003;4(2):121–32. Trenkwalder C, Paulus W. Why do restless legs occur at rest? — pathophysiology of neuronal structures in RLS. Neurophysiology of RLS (part 2). Clin Neurophysiol 2004;115:1975–88. Trenkwalder C, Stiasny-Kolster K, Kupsch A, Oertel WH, Koester J, Reess J. The German RLS-Pramipexole Study Group. Controlled withdrawal of pramipexole after 6 months of open-label treatment in patients with restless legs syndrome. Mov Disord 2006;21(9):1404–10. Trenkwalder C, Hening WA, Montagna P, Oertel WH, Allen RP, Walters AS, et al. Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. Mov Disord 2008;23(16):2267–302. von Scheele C, Kempi V. Long-term effect of dopaminergic drugs in restless legs: a 2-year follow-up. Arch Neurol 1990;47(11):1223–4. Winkelman JW, Johnston L. Augmentation and tolerance with long-term pramipexole treatment of restless legs syndrome (RLS). Sleep Med 2004;5(1):9-14. Winkelman JW, Sethi KD, Kushida CA, Becker PM, Koester J, Cappola JJ, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurol 2006;67(6):1034–9.
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Proposed dose equivalence between clonazepam and pramipexole in patients with restless legs syndrome Hideto Shinno a,⁎, Yasunori Oka b, Manabu Otsuki c, Satoshi Tsuchiya d, Soichi Mizuno e, Seiichi Kawada f, Toshihiko Innami g, Akira Sasaki h, Takashi Hineno i, Tetsuro Sakamoto j, Yasushi Inami k, Yu Nakamura a, Jun Horiguchi l a
Department of Neuropsychiatry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kida, Kagawa 761-0793, Japan Department of Sleep Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan c Otsuki Sleep Clinic, 4-16 Wase, Fukushima, Fukushima 960-8044, Japan d Tsuchiya Clinic, 2-3-11 Uemachi, Ube, Yamaguchi 755-0051, Japan e Department of Psychiatry, Fukuyama Medical Center, 14-17 Okinogamicho, Fukuyama, Hiroshima 720-8520, Japan f Kochi Kagamigawa Hospital, 270 Joyama, Kochi, Kochi 780-8037, Japan g Innami Ophthalmology and Neurology Clinic, 380-1 Taguchi, Ohzu, Ehime 795-0063, Japan h Saijo Dozen Hospital, 3290-1 Iiokajizouhara, Saijo, Ehime 793-0010, Japan i Hineno Clinic, 4-5-1 Umagoe, Imabari, Ehime 794-0062, Japan j Yuai Hospital, 728-1 Nakashou, Higashi-miyoshi, Miyoshi, Tokushima 779-4703, Japan k Department of Psychiatry, Ehime Rosai Hospital, 13-27 Minami-komatsubara, Niihama, Ehime 792-8550, Japan l Department of Psychiatry, Shimane University Faculty of Medicine, 89-1 Enya, Izumo, Shimane 693-8501, Japan b
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Article history: Received 25 December 2009 Received in revised form 12 January 2010 Accepted 9 February 2010 Available online 13 February 2010 Keywords: Clinical Global Impressions — Severity of illness (CGI-S) Clonazepam Equivalent ratio Pramipexole Restless legs syndrome (RLS) The International Restless Legs Syndrome Study Group rating scale (IRLS)
a b s t r a c t Background: Dopamine agonists are accepted as the first-line medications for restless legs syndrome (RLS). In some Asian countries, clonazepam is one of the prevalent medications for RLS because of its effect on sleep disturbances. To date, there have not been any studies that examined equivalent doses of pramipexole and clonazepam. To evaluate equivalent doses of pramipexole and clonazepam in RLS, we investigated the efficacy and tolerability after conversion from clonazepam to pramipexole, and examined dose equivalence between the two prescriptions. Methods: In a prospective, open-label, multicenter study, 26 RLS patients treated with clonazepam (mean age: 69.2 ± 11.0 years old) were enrolled and then rapidly switched to pramipexole using a conversion calculation of 4:1 for daily doses. Then the daily dose of pramipexole was up titrated or tapered by 0.125 mg/ day at each subsequent examination. RLS symptoms and daytime somnolence were evaluated using the International RLS Study Group rating scale (IRLS), Clinical Global Impressions — Severity of illness (CGI-S) and the Epworth Sleepiness Scale (ESS), respectively. Results: Conversion from clonazepam to pramipexole resulted in significant reductions of IRLS (16.3 ± 8.7 to 9.1 ± 6.3) and ESS (6.5 ± 4.2 to 4.4 ± 3.2). CGI scores demonstrated improvement after conversion. In 4 patients (15%), adverse events such as somnolence, sensation of oppression in the lower limbs, diarrhea, or nausea were present. Correlation analysis demonstrated a significant relationship between these daily doses. Spearman's correlation coefficient was 0.662. Our study, however, has some limitations since it is an openlabel trial and includes only 26 patients. Further studies using a double-blind design or a crossover design are recommended. Conclusions: Statistical analysis demonstrated a 4:1 conversion for clonazepam to pramipexole. When switchover from clonazepam to pramipexole is done, this conversion ratio may be helpful to determine the initial dose of pramipexole for treating RLS. © 2010 Elsevier Inc. All rights reserved.
Abbreviations: CGI-S, Clinical Global Impression of Severity; ESS, Epworth Sleepiness Scale; IRLS, International Restless Legs Syndrome Rating Scale; MDS, Movement Disorder Society; PLM, periodic limb movements; RLS, restless legs syndrome. ⁎ Corresponding author. Department of Neuropsychiatry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793, Japan. Tel.: + 81 87 891 2165; fax: + 81 87 891 2168. E-mail address: [email protected] (H. Shinno). 0278-5846/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2010.02.011
1. Introduction Restless legs syndrome (RLS) is a neurological disorder characterized by an urge to move, and usually associated with uncomfortable leg sensations (Montplaisir et al., 2005). The National Institutes of Health RLS workshop (Allen et al., 2003) has defined the diagnostic
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criteria. The four essential criteria are: (1) an urge to move, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs; (2) the urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying and sitting; (3) the urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as activity continues; and (4) the urge to move or unpleasant sensations are worse in the evening or night than during the day or occur only in the evening or night. Most RLS patients report difficulties falling asleep (Montplaisir et al., 2005). It is also difficult for patients with RLS to maintain their sleep because they awaken with unpleasant sensations shortly after sleep onset (Montplaisir et al., 2005). As a consequence of frequent arousals from nocturnal sleep, patients often experience excessive daytime fatigue and somnolence. It is, therefore, mandatory to treat RLS adequately. Dopaminergic medications are now widely prescribed for RLS treatment. Initially, the short-term efficacy of L-dopa was well documented. Polysomnographic studies showed that L-dopa administration induced a significant reduction in RLS symptoms present at bedtime as well as reducing periodic limb movements (PLM) throughout the night (Brodeur et al., 1988). Varying degrees of longterm benefit from L-dopa, however, have been found, ranging from 85% (von Scheele and Kempi, 1990) to 31% (Earley and Allen, 1996) after a few years. Several adverse effects have been reported in patients treated with L-dopa, such as nausea, vomiting, tachycardia, orthostatic hypotension, hallucinations, and insomnia. Morning rebound and RLS augmentation are known as more specific adverse effects. Dopaminergic agonists are now considered the first-line treatment for RLS because they are more effective and produce fewer adverse effects. In this decade, pramipexole, non-ergoline derivative agonists for dopamine D2/D3 receptor, have been studied for RLS treatment (Montplaisir et al., 1999). Results from several double-blind, placebo-controlled studies have demonstrated the superiority of pramipexole for the broad range of RLS symptoms (Ferini-Strambi et al., 2008; Oertel et al., 2007; Winkelman et al., 2006). There have also been several long-term studies demonstrating sustained efficacy of pramipexole in RLS (Silber et al., 2003; Winkelman and Johnston, 2004). Several studies have shown that benzodiazepines such as clonazepam improve the quality of sleep and reduce periodic limb movements during sleep (PLMs) as well as PLMs-associated arousals in patients with RLS, as has been reported its acute therapeutic efficacy regarding insomnia (Saletu et al., 2001). Clonazepam is prescribed to improve sleep continuity and used as an adjunct treatment because dopaminergic agents sometimes worsen insomnia. However, regarding subjective RLS symptoms, sufficient studies demonstrating the effects of clonazepam have not been conducted (Trenkwalder et al., 2008), even though clonazepam prescription is prevalent in some countries of Asia and Europe. To date, there have not been any studies on the conversion to nonergot dopamine agonists in patients with RLS, although several articles have reported the conversion from ergot to non-ergot dopamine agonists in patients with advanced Parkinson's disease (Goetz et al., 1999; Hanna et al., 2001). Furthermore, there have not been any studies examining equivalent doses of pramipexole and clonazepam. The aim of this study is to evaluate equivalent doses of pramipexole and clonazepam in Japanese patients with RLS, using efficacy and tolerability after switching from clonazepam to pramipexole as indications of dose equivalence.
2. Methods 2.1. Study design The study was conducted at 11 centers in Japan. This study was a prospective, open-label study design to assess the therapeutic equiva-
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lence of progressive switching from clonazepam to pramipexole. Data were collected between September 2008 and September 2009. 2.2. Patients Twenty-six patients with idiopathic and secondary RLS were enrolled in this study. The diagnosis of RLS was made according to the essential criteria established by the International RLS Study Group (Allen et al., 2003). All patients were treated with therapeutic levels of clonazepam monotherapy, and required a switch for one or more of the following reasons: i) inability to achieve satisfactory symptom control due to doselimiting side effects experienced with clonazepam; ii) inability to adequately tolerate clonazepam monotherapy even in the presence of acceptable symptom control; iii) patients who, despite achieving adequate symptom control, were prone to recurrent clinical conditions requiring treatment with drugs known to interact with clonazepam. Patients were eligible if (i) they were aged ≥20 years, (ii) clonazepam had been prescribed (≤2.0 mg/day), (iii) daily doses of clonazepam did not change for more than 4 weeks, and no other drugs were prescribed for RLS. Patients were excluded for pregnancy or breast-feeding; for having contraindications to pramipexole; for comorbidity with other sleep disorders. Patients were also excluded from this study if the causes of RLS were pregnancy, renal failure, artificial dialysis, or drugs such as neuroleptics and antidepressants. The local institutional research boards approved this study. All patients gave informed consent according to institutional guidelines and the tenets of the Declaration of Helsinki. 2.3. Treatment If patients had been prescribed less than 1 mg/day of clonazepam, clonazepam was discontinued and pramipexole was prescribed. The initial daily dose of pramipexole was calculated using a conversion of 1:4 for clonazepam dose (Fig. 1A). However, if the patients had been prescribed 1 mg/day or over 1 mg/day of clonazepam, two protocols for switching were adopted (Fig. 1B). One protocol was the rapid switch, which was the same as for patients pretreated with a lower dose of clonazepam (Fig. 1B-(a)). The other was gradual switching. Intermediate doses of clonazepam and pramipexole were prescribed for a week followed by a complete switch to pramipexole (Fig. 1B-(b)). As RLS symptoms and adverse effects were observed, the dose of pramipexole was titrated. The daily dose of pramipexole was up titrated or tapered by 0.125 mg/day at each subsequent examination. 2.4. Measurements We evaluated the severity of RLS symptoms using the International Restless Legs Syndrome Rating Scale (IRLS) (The International Restless Legs Syndrome Study Group, 2003). Daytime somnolence was measured by the Epworth Sleepiness Scale (ESS) (Johns, 1991). We objectively evaluated severity using the Clinical Global Impression of Severity (CGI-S). We assessed the International RLS Study Group rating scale (IRLS), ESS, and CGI-S at each examination. Adverse events were also elicited at each examination. 2.5. Data analysis To assess changes in scores on the IRLS, the ESS, and CGI-S, we used a Wilcoxon's signed-rank test. According to the severity of RLS symptoms, patients were divided into four categories: none or mild (IRLS score 0–10), moderate (IRLS score 11–20), severe (IRLS score 21–30), and very severe (IRLS score 31–40). The distribution of patients across severity categories was compared before and after switching using the chi-square test. The relationship between the daily doses of clonazepam and those of pramipexole after conversion was analyzed using Spearman's correlation.
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Fig. 1. Mode of conversion from clonazepam to pramipexole. (Panel A) If patients had been prescribed less than 1 mg/day of clonazepam, clonazepam was discontinued and pramipexole was prescribed. The initial daily dose of pramipexole was calculated using a conversion of 1:4 for the clonazepam dose. (Panel B) If the patients had been prescribed 1 mg/day or over 1 mg/day of clonazepam, two protocols for switching were adopted. One protocol was the rapid switch, which was the same as adopted for patients pretreated with a lower dose of clonazepam (as shown in B-(a)). The other protocol was gradual switching. Intermediate doses of clonazepam and pramipexole were prescribed for a week followed by a complete switch to pramipexole (as shown in B-(b)).
15.4± 9.0 and 6.5 ± 4.2, respectively. The mean daily dose of clonazepam was 0.82 ± 0.31 (0.5–1.5 mg/day).
3. Results 3.1. The demography and baseline characteristics of subjects (Table 1) Twenty-six patients were enrolled in this study (14 males and 12 females). Twenty-three patients had primary RLS and three patients had secondary RLS. The mean age was 69.2 ± 11.0 years old (44 to 86 years old). The mean duration of RLS was 65.0 ± 72.8 months. The mean IRLS score and ESS score before pramipexole prescription were Table 1 The demography and baseline characteristics of the subjects. Gender, n (%) Male 14 (53.8%) Female 12 (46.2%) Mean age (years old) 69.2 ± 11.0 [44–86] Age, n (%) b65 y.o. 7 (26.9%) ≥65 y.o. 19 (73.1%) Duration of RLS (months) 65.0 ± 72.8 [2–244] Mean total IRLS score 15.4 ± 9.0 [0–33] Mean CGI-S score 3.8 ± 1.2 [1–6]
Mean ESS score 6.5 ± 4.2 [0–17] Severity of RLS symptoms, n (%) Mild 8 (30.8%) Moderate 9 (34.6%) Severe 8 (30.8%) Very severe 1 (3.8%)
3.2. The RLS symptoms Of the 26 subjects, 24 patients completed this study. The severity of RLS symptoms before and after conversion was compared in these 24 patients. The mean IRLS score was 16.3 ± 8.7 before conversion. After conversion to pramipexole was accomplished, the mean IRLS score was 9.1 ± 6.3, which was a significant decrease (p = 0.002) (Fig. 2). When the distribution of severity categories (none or mild, moderate, severe, and very severe) before switching was compared with that after conversion to pramipexole, we found a significant difference between the two periods (p = 0.016) (Table 2).
Classification of RLS, n (%) Primary 23 (88.5%) Secondary 3 (11.5%) Daily dose of clonazepam (mg/day) Mean 0.82 ± 0.31 [0.5–1.5] Daily dose of clonazepam, n (%) 0.5 mg/day 11 (36%) 0.75 mg/day 1 (5%) 1.0 mg/day 12 (50%) 1.5 mg/day 2 (9%)
Values represent the mean with standard deviation. Range is shown in a bracket parenthesis.
Fig. 2. Effect of pramipexole on the RLS symptoms. RLS symptoms were evaluated using International Restless Legs Syndrome Study Group rating scale (IRLS) [16]. The IRLS scores before the switch and those after the switch to pramipexole were compared. Data were analyzed by Wilcoxon's signed-rank test. **p b 0.01.
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Table 2 Comparison of severity category. Severity categories of RLS symptoms None or mild
Before switch After switch
Moderate
Severe
Very severe
IRLS score
IRLS score
IRLS score
IRLS score
0–10
11–20
21–30
31–40
6 (25.0%) 16 (66.7%)
9 (37.5%) 7 (29.2%)
8 (33.3%) 1 (4.2%)
1 (4.2%) 0 (0%)
The severity of restless legs syndrome (RLS) symptoms was evaluated with the International Restless Legs Syndrome Rating Scale (IRLS) [16]. Patients were divided into 4 categories based on symptom severity. The categories were defined as “none or mild” (IRLS score 0–10), “moderate” (IRLS score 11–20), “severe” (IRLS score 21–30), and “very severe” (IRLS score 31–40). The distributions of severity categories before and after the switch to pramipexole were compared using the chi-square test. *p b 0.05.
Fig. 4. Global Impression of the severity of illness. Global impression of the severity of illness was evaluated using Clinical Global Impression — Severity of illness (CGI-S). The CGI-S scores before the switch and those after the switch to pramipexole were compared. Data were analyzed by Wilcoxon's signed-rank test. **p b 0.01.
3.3. The daytime somnolence
4. Discussion
The mean ESS score was 6.5 ± 4.4 before conversion. After conversion to pramipexole was accomplished, the mean ESS score was 4.4 ± 3.2, which was a significant decrease (p = 0.004) (Fig. 3).
Restless legs syndrome is relatively common, with a prevalence ranging from 2.5% to 10% in the general population (Allen et al., 2005; Rothdach et al., 2000). Although the pathophysiology of RLS is not yet sufficiently understood, evidence has shown that a dopaminergic pathway may be involved (Allen, 2004; Trenkwalder and Paulus, 2004). The Movement Disorder Society (MDS) commissioned a task force to perform an evidence-based review of current treatment strategies, and non-ergot-derived dopamine agonists were indicated to be efficacious treatment for RLS [13]. Pramipexole, a non-ergoline dopamine agonist, was shown to be successful in the treatment of RLS in double-blind, placebo-controlled, crossover, randomized studies enrolling large numbers of subjects (Ferini-Strambi, et al. 2008; Montplaisir et al., 1999; Oertel et al., 2007; Partinen et al., 2006; Trenkwalder et al., 2006; Winkelman et al., 2006). Periodic limb movements during sleep (PLMs) is most often associated with RLS, while a frequent comorbidity with other sleep disorders, such as sleep apnea, narcolepsy, parasomnia, has also been reported (Boehm et al., 2009; Hornyak et al., 2006). Disturbances with a significant impact on the quality of life as well as increased PLM indices (number of PLM per hour of time in bed) are common in RLS (Boehm et al., 2009). Some studies have reported that clonazepam is prescribed to improve sleep continuity in patients with RLS (Boghen et al., 1986; Matthews, 1979; Montagna et al., 1984; Read et al., 1981) because dopaminergic agents sometimes worsen insomnia. There is,
3.4. The adverse events We observed the physical condition and examined adverse events at every visit. Of the 4 patients who exhibited adverse events, two patients required the discontinuation of pramipexole due to mild nausea (daily dose of pramipexole: 0.25 mg/day) or diarrhea (daily dose of pramipexole: 0.25 mg/day), which lasted for 1 day and 3 days, respectively. The others transiently complained of somnolence (daily dose of pramipexole: 0.25 mg/day) and sensation of oppression in the legs (daily dose of pramipexole: 0.125 mg/day), but continued pramipexole treatment.
3.5. The objective impressions of severity The mean CGI-S scores at baseline and after conversion were 3.9 ± 1.3 and 2.7 ± 0.9, respectively (Fig. 4). Wilcoxon's signed-rank test demonstrated a significant decrease in CGI-S score (p = 0.004).
3.6. The equivalent ratio between clonazepam and pramipexole The relationship between daily doses of clonazepam and those of pramipexole was investigated (Table 3). Correlation analysis demonstrated a significant relationship between these daily doses. Spearman's correlation coefficient was 0.662 (p b 0.001). Using 4:1 as the equivalent dose ratio of clonazepam to pramipexole was valid.
Fig. 3. Comparison of daytime somnolence. Daytime somnolence was evaluated using Epworth Sleepiness Scale (ESS) [17]. The ESS scores before the switch and those after the switch to pramipexole were compared. Data were analyzed by Wilcoxon's signedrank test. **p b 0.01.
Table 3 The equivalent ratio between clonazepam and pramipexole.
The relationship between daily doses of clonazepam and those of pramipexole was investigated. Correlation analysis was carried out using Spearman's test. Spearman's correlation coefficient was 0.662 (p b 0.001). Shaded cells indicate the daily dose ratio of clonazepam 4 to pramipexole 1.
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however, no clear evidence that subjective or objective PLM measures of therapeutic benefit have been achieved. These studies did not measure or discuss daytime somnolence, although clonazepam has a very prolonged effect and may cause such somnolence. Although dopamine agonists such as pramipexole may cause daytime sleepiness, previous studies in patients with RLS demonstrated that there was no significant difference in ESS score between pramipexole and placebo (Partinen et al., 2006; Winkelman et al., 2006; Trenkwalder et al., 2006). As indicated in an evidence-based review established by the MDS-commissioned task force (Trenkwalder et al., 2008), the therapeutic effect of clonazepam on RLS may be investigational, although patients with subjective and/or objective sleep disturbances may indeed require treatment such as clonazepam. The strategy for conversion from clonazepam to dopaminergic agents should, therefore, be considered, when clonazepam fails to improve RLS symptoms sufficiently, or induces adverse effects. It remains controversial whether rapid switch is preferable to slow titration. There have been several studies on switching protocol in patients with Parkinson's disease (Goetz et al., 1999; Hanna et al., 2001), although switching protocol has not been investigated in patients with RLS. Reports have shown that rapid conversion was safer, and that some patients with slow titration experienced enhanced parkinsonism (Goetz et al., 1999). Based on these findings, we rapidly switched to pramipexole in principle and pramipexole dose was calculated using a daily milligram conversion of 1:4 for clonazepam dose. However, in patients pretreated with higher doses of clonazepam (over 1 mg/day), half daily doses of clonazepam were administered for a week instead of rapid discontinuation because it was necessary to prevent withdrawal symptoms. In the present study, a smaller proportion of subjects (4 of 26: 15.4%) exhibited adverse events. We consider that conversion to pramipexole may be relatively safe, although the lower percentage of adverse effects may be due to the lower daily doses of pramipexole prescribed for patients with RLS. To our knowledge, there have not been any studies that investigated the switchover from clonazepam to pramipexole in patients with RLS. The present study demonstrates the important and practical findings that had not been investigated in patients with RLS. First, the comparison of efficacy and safety between pramipexole and clonazepam seems to be meaningful because there have been no comparative trials to agents other than placebo. We have demonstrated that conversion to pramipexole resulted in improvements of RLS symptoms and daytime somnolence. We consider that pramipexole may be preferable to clonazepam. Second, we have defined a conversion ratio to facilitate switching from clonazepam to pramipexole in a simple, safe, and effective manner for patients with RLS. Statistical analysis confirmed that a 4:1 conversion ratio for clonazepam to pramipexole is appropriate. Our study, however, has some limitations since it is an open-label trial and includes only 26 patients. Further studies using a double-blind design or a crossover design are recommended. 5. Conclusion Conversion to pramipexole was demonstrated to be effective for RLS symptoms and daytime somnolence, and to be well tolerated. When switchover from clonazepam to pramipexole is required, a 4:1 conversion ratio for clonazepam to pramipexole may be helpful to determine the initial dose of pramipexole for treating RLS. Acknowledgements We certify that there was no financial support for this study. The authors are grateful to Dr. Tatsuru Horikoshi (Horikoshi Shinshin Clinic, Fukushima, Japan) and Dr. Hidehisa Yamashita (Hiroshima University Graduate School of Medicine, Hiroshima, Japan) for their useful suggestions.
References Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med 2004;5(4):385–91. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisir 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. 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(11):1286–92. Boehm G, Wetter TC, Trenkwalder C. Periodic leg movements in RLS patients as compared to controls: are there differences beyond the PLM index. Sleep Med 2009;10:566–71. Boghen D, Lamothe L, Elie R, Godbout R, Montplaisir J. The treatment of the restless legs syndrome with clonazepam: a prospective controlled study. Can J Neurol Sci 1986;13(3):245–7. Brodeur C, Montplaisir J, Godbout R, Marinier R. Treatment of restless legs syndrome and periodic limb movements during sleep with L-dopa: a double-blind, controlled study. Neurology 1988;38:1845–8. Earley CJ, Allen RP. Pergolide and carbidopa/levodopa treatment of the restless legs syndrome and periodic leg movements in sleep in a consecutive series of patients. Sleep 1996;19(10):801–10. Ferini-Strambi L, Aarskog D, Partinen M, Chaudhuri KR, Sohr M, Verri D, et al. Effect of pramipexole on RLS symptoms and sleep: a randomized, double-blind, placebocontrolled trial. Sleep Med 2008;9(8):874–81. Goetz CG, Blasucci L, Stebbins GT. Switching dopamine agonists in advanced Parkinson's disease. Neurology 1999;52(6):1227–9. Hanna PA, Ratkos L, Ondo WG, Jankovic J. Switching from Pergolide to pramipexole in patients with Parkinson's disease. J Neural Transm 2001;108(1):63–70. Hornyak M, Feige B, Riemann D, Voderholzer U. Periodic leg movements in sleep and periodic limb movement disorder: prevalence, clinical significance and treatment. Sleep Med Rev 2006;10:169–77. Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991;14(6):540–5. Matthews WB. Treatment of the restless legs syndrome with clonazepam. Br Med J 1979;1(6165):751. Montagna P, de Bianchi LS, Zucconi M, Cirignotta F, Lugaresi E. Clonazepam and vibration in restless legs syndrome. Acta Neurol Scand 1984;69(6):428–30. Montplaisir J, Nicolas A, Denesle R, Gomez-Mancilla B. Restless legs syndrome improved by pramipexole: a double-blind randomized trial. Neurology 1999;52(5):938–43. Montplaisir J, Allen RP, Walters AS, Ferini-Strambi L. Restless legs syndrome and periodic limb movements during sleep. In: Kryger M, Roth T, Dement W, editors. Principles and practice of sleep medicine. 4th edition. Philadelphia: Elsevier Saunders; 2005. p. 839–52. Oertel WH, Stiasny-Kolster K, Bergtholdt B, Hallström Y, Albo J, Leissner L, et al. The Pramipexole RLS Study Group. Efficacy of pramipexole in restless legs syndrome: a six-week, multicenter, randomized, double-blind study. Mov Disord 2007;22(2): 213–9. Partinen M, Hirvonen K, Jama L, Alakuijala A, Hublin C, Tamminen I, et al. Efficacy and safety of pramipexole in idiopathic restless legs syndrome: a polysomnographic dose-finding study — the PRELUDE study. Sleep Med 2006;7:407–17. Read DJ, Feest TG, Nassim MA. Clonazepam: effective treatment for restless legs syndrome in uremia. Br Med J 1981;283(6296):885–6. Rothdach AJ, Trenkwalder C, Haberstock J, Keil U, Berger K. Prevalence and risk factors of RLS in an elderly population: the MEMO study. Memory and Morbidity in Augsburg Elderly. Neurology 2000;54(5):1064–8. Saletu M, Anderer P, Saletu-Zyhlarz G, Prause W, Semler B, Zoghlami A, et al. Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD): acute placebocontrolled sleep laboratory studies with clonazepam. Eur Neuropsychopharmacol 2001;11(2):153–61. Silber MH, Girish M, Izurieta R. Pramipexole in the management of restless legs syndrome. Sleep 2003;26(7):819–21. The International Restless Legs Syndrome Study Group. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2003;4(2):121–32. Trenkwalder C, Paulus W. Why do restless legs occur at rest? — pathophysiology of neuronal structures in RLS. Neurophysiology of RLS (part 2). Clin Neurophysiol 2004;115:1975–88. Trenkwalder C, Stiasny-Kolster K, Kupsch A, Oertel WH, Koester J, Reess J. The German RLS-Pramipexole Study Group. Controlled withdrawal of pramipexole after 6 months of open-label treatment in patients with restless legs syndrome. Mov Disord 2006;21(9):1404–10. Trenkwalder C, Hening WA, Montagna P, Oertel WH, Allen RP, Walters AS, et al. Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. Mov Disord 2008;23(16):2267–302. von Scheele C, Kempi V. Long-term effect of dopaminergic drugs in restless legs: a 2-year follow-up. Arch Neurol 1990;47(11):1223–4. Winkelman JW, Johnston L. Augmentation and tolerance with long-term pramipexole treatment of restless legs syndrome (RLS). Sleep Med 2004;5(1):9-14. Winkelman JW, Sethi KD, Kushida CA, Becker PM, Koester J, Cappola JJ, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurol 2006;67(6):1034–9.