Abstract
Background: Restless legs syndrome (RLS) is characterized by leg paresthesia associated with an irresistible urge to move. Currently used dopaminergic agents, such as levodopa, pergolide, and bromocriptine, offer incomplete control of sensory and motor symptoms and induce severe side effects.
Objective: To assess the safety and efficacy of pramipexole, a full D3-receptor agonist, in the treatment of RLS.
Methods: Ten RLS patients were studied before and after two 1-month treatments (placebo and pramipexole) administered in a double-blind crossover fashion. The severity of sensory and motor manifestations was assessed by 1 week of home questionnaires and 2 consecutive nights of sleep laboratory recordings. The indexes of periodic leg movement during sleep (PLMS) and during wakefulness (PLMW) were used as primary outcome variables.
Results: Pramipexole dramatically reduced the PLMS index to normal values (Wilcoxon, p = 0.005). The PLMW index was also significantly reduced (Wilcoxon, p = 0.007). Pramipexole also alleviated leg discomfort at bedtime and during the night as measured by the home questionnaires.
Conclusions: Pramipexole is the most potent therapeutic agent ever tested for RLS. Measures of both sensory and motor functions returned to normal values after treatment. Moreover, these results further support the hypothesis that D3 receptors play a major role in the physiopathology of this condition.
Restless legs syndrome (RLS) is a condition characterized by unpleasant limb sensations occurring at rest and associated with an irresistible urge to move.1-3 Recently a large international RLS study group4 defined the following four criteria as essential for diagnosis: 1) leg paresthesia/dysesthesia associated with a desire to move the extremities, 2) motor restlessness, 3) worsening of symptoms at rest with at least temporary relief by activity, and 4) worsening of symptoms in the evening or during the night. Sleep laboratory investigations have shown the presence of periodic leg movements during sleep (PLMS) in more than 80% of RLS patients.5,6 PLMS are best described as rhythmic extensions of the big toe and foot that may or may not be associated with flexions at the knee or hip level. PLMS are recorded and scored according to a standard method developed by Coleman,7 which is based on EMG recordings from the right and left anterior tibialis muscles. An index of five movements or more per hour of sleep is considered pathologic. RLS patients also have PLMs during wakefulness (PLMW).8
Several treatments have been used to treat RLS. Benzodiazepines, including clonazepam, nitrazepam, temazepam, and triazolam, have been used to treat RLS and PLMS9-11 and have been shown to improve the quality of nocturnal sleep. However, PLMS indexes remain above normal with benzodiazepine treatment. In addition, benzodiazepines are potent CNS depressants; they often cause daytime sleepiness and may induce or aggravate sleep apnea syndrome.12
The therapeutic action of opioids was mentioned in the original description of RLS by Ekbom.1 More recently, this effect was further documented in open clinical trials and a placebo-controlled study.13,14 However, the risk for abuse and the danger of addiction limit considerably the clinical use of opioids in RLS and PLMS.
Dopaminergic agents are now considered the treatment of choice for RLS. Levodopa given with a peripheral decarboxylase inhibitor is effective in treating RLS and PLMS.15-20 Long-term follow-up studies showed persistent beneficial effects of levodopa in RLS.18,19 However, when levodopa is administered only at bedtime,16 a rebound of PLMS is often observed in the last part of the night. In addition, Guilleminault et al.20 reported that 35% of RLS patients chronically treated with levodopa developed morning restlessness that completely disappeared within 2 to 6 days after discontinuing treatment. More recently, Allen and Earley21 reported a de novo occurrence of late-afternoon leg restlessness in patients who received levodopa at bedtime and during the night. In clinical practice, rebound restlessness often leads to additional administration of levodopa during the daytime or to interruption of treatment.
D2-receptor agonists, such as bromocriptine22 and pergolide,23-25 are also effective in treating RLS. However, both are ergoline derivatives and are associated with major and frequent side effects that limit their clinical usefulness in the treatment of RLS. In addition, some degree of subjective and objective manifestations of RLS persists after treatment with either drug. Recently, a new D3-receptor agonist, pramipexole, was developed and found to be effective in the treatment of patients with PD.26 Pramipexole is not an ergoline derivative and was the antiparkinsonian drug best tolerated by parkinsonian patients.
The aim of the present study was to examine the efficacy and safety of pramipexole in patients with RLS and PLMS. Based on the results obtained with other dopaminergic drugs in RLS and with pramipexole in PD, pramipexole was expected to be both effective and produce fewer side effects than the other current treatments for RLS.
Methods.
Patient population.
Ten patients were selected for this study based on the following criteria: 1) the presence of the four clinical manifestations mandatory for the diagnosis of RLS as defined by the International RLS Study Group,4 and 2) the presence of RLS symptoms interfering with sleep onset or with the continuity of sleep more than three nights per week for at least 1 year. The study enrolled both men and women aged 20 to 65 years. Written informed consent was obtained from each patient, and the study was approved by the ethics committee.
Patients were excluded for any of the following reasons: 1) the presence of any condition known to be associated with RLS, specifically, anemia, chronic renal failure, or peripheral neuropathy or myelopathy; these conditions were ruled out based on clinical examination and appropriate blood testing; 2) a PLMS index lower than 10 per hour of sleep (as measured at baseline in the sleep laboratory); 3) the presence of any other sleep disorders such as narcolepsy, REM sleep behavior disorder, or sleep apnea syndrome; none of the patients could have an index of respiratory events (number of apneas + hypopneas) greater than five per hour of sleep or a minimal O2 saturation lower than 90%; 4) the use of drugs known to influence sleep architecture or motor manifestations during sleep within 2 weeks before baseline recordings.
Study design.
This was a 10-week, double-blind, placebo-controlled, crossover study. Patients underwent two 4-week treatments, one with placebo and one with pramipexole, with a 2-week washout period between treatments. Patients were evaluated in four two-night polysomnographic recordings in the sleep laboratory: 1) at baseline (to determine baseline values and whether the patient met all inclusion/exclusion criteria), 2) at the end of the initial treatment (end of week 4), 3) at the end of the washout period (end of week 6), and 4) at the end of the crossover treatment (end of week 10).
Sleep was recorded, and sleep stages were scored according to the method developed by Rechtschaffen and Kales27 using 20-second epochs. Right and left anterior tibialis EMGs were recorded to score PLMS according to the method developed by Coleman.7 Movements were counted only if they had a duration of 0.5 to 5 seconds, separated by intervals of 4 to 90 seconds, and if they occurred in series of at least four consecutive movements. The PLMS index represents the number of PLMs per hour of sleep. PLMs were also scored during periods of wakefulness during the night (PLMW) using the same method. The PLMW index represents the number of PLMs per hour of wakefulness during the nocturnal polygraphic recording.
In addition, every patient filled out evening and morning questionnaires inquiring about leg restlessness during the daytime and in the evening (evening questionnaires) or leg restlessness at bedtime and upon awakening during the night (morning questionnaires) for 1 week before each of the four recording sessions. In these questionnaires, restlessness was rated as follows: absence of restlessness = 0; mild = 1; moderate = 2; and severe = 3 (daily score = 0 to 3, weekly score = 0 to 21).
The primary outcome measures were the PLMS and PLMW indexes from the nocturnal polygraphic recordings and the degree of leg restlessness as evaluated by the home questionnaires. The secondary efficacy measures were the sleep latency and sleep efficiency from the nocturnal polygraphic recordings. The adequacy of the sample size was estimated by using the results of a prior study17 on the effect of levodopa on PLMS number and index using a minimum difference of 70% from placebo values.
Drug administration protocol.
The pramipexole tablets and identical-looking placebo tablets were taken 1 hour before bedtime. The initial dosage of pramipexole was 0.375 mg/d. After 1 week the dosage was increased to 0.75 mg/d and, after the second week, to 1.5 mg/d. At each dosage increase, patients were instructed to go back to the previous dosage if they experienced persistent side effects related to the medication. The patients, investigators, and sponsor were all blinded to treatment sequence. Individuals were randomly assigned to groups. The allocation to the two treatment sequences was generated electronically by the department responsible for packaging new investigational drugs and was maintained concealed by coded packaging and papers. No unblinding occurred before study completion.
Clinical evaluation of efficacy and safety.
In addition to polysomnographic recordings, patients were seen every 2 weeks throughout the study to assess therapeutic effects as well as side effects of the treatments. These assessments were made by a sleep specialist who was blind with regard to treatment.
Data analyses.
Results of the questionnaires and of nocturnal polygraphic recordings (sleep architecture variables and PLMS-PLMW variables) obtained in the four conditions (baseline, placebo, withdrawal, and pramipexole) were analyzed using nonparametric crossover tests28 simultaneously assessing the carryover and treatment effects with Mann-Whitney U tests.
Results.
Disposition of patients.
Ten patients, 5 men and 5 women, aged 30 to 61 years (mean 49.3 ± 11.5 years) completed the study. In addition, one patient completed the baseline recording, but on the first day of her first treatment (pramipexole) she decided to withdraw from the study because of an incompatibility between the requirements of the study and her work and vacation schedule. She was rejected from the data analysis. Four patients were taking clonazepam, three were taking levodopa, and one was taking pergolide before entering the study; these treatments were interrupted at least 2 weeks before baseline recording, as required by the protocol. As a result of individual randomization and the dropout subject (figure 1), six patients received placebo as their first treatment, and four patients received pramipexole as their first treatment instead of five subjects in each treatment sequence. In the pramipexole treatment period, six patients increased the dosage to 1.5 mg/d, whereas four patients either remained on the 0.75 mg/d dosage or returned to the 0.75 mg/d dosage because of nausea or daytime fatigue. Otherwise, all measures were performed according to the protocol. There was no carryover effect for any of the measures studied.
Figure 1. Study profile diagram: double-blind, crossover randomized trial.
Home questionnaires.
Table 1 shows the results of home questionnaires completed for 1 week before each recording session. Results obtained at baseline show that leg restlessness is present during daytime but worsens in the evening, at bedtime, and during the night (Friedman analysis of variance: p = 0.002). However, severity of leg restlessness was not significantly different between evening, bedtime, or nighttime. Pramipexole administration produced a significant decrease in subjective leg restlessness during the daytime (p = 0.014), in the evening (p = 0.05), at bedtime (p = 0.003), and during the night (p = 0.009)—a difference of 72 to 84% (depending on the time of day) compared with placebo. A small decrease in nighttime restlessness was seen during withdrawal compared with baseline. However, this change is small compared with the treatment effect and is not due to a carryover effect.
Subjective leg restlessness (home questionnaires) for 10 restless legs syndrome (RLS) patients during daytime, evening, bedtime, and nighttime in the four conditions (mean ± standard deviation)
Sleep architecture and PLMS-PLMW.
There were no significant differences between pramipexole and placebo for variables evaluating the continuity of sleep, such as sleep latency, total sleep time, sleep efficiency, and number of awakenings, or for the percentages of non-REM sleep stages. However, there were differences for REM sleep variables. Compared with placebo, pramipexole significantly increased REM sleep latency (153.6 ± 83.0 minutes versus 101.8 ± 20.0 minutes; p = 0.02) and decreased total REM sleep time (61.3 ± 27.8 minutes versus 84.0 ± 25.9 minutes; p = 0.03), as well as the percentage of time spent in REM sleep (14.7 ± 6.1% versus 20.7 ± 4.3%; p = 0.01).
More importantly, pramipexole produced a 98% decrease in both the number and the index of PLMS compared with placebo (table 2). During pramipexole treatment, the PLMS index returned to a normal value (below 5). Pramipexole also significantly decreased the number of PLMS associated with arousals as well as the number and the index of PLMW. Figure 2 illustrates the PLMS index obtained for each patient at all four polysomnographic recording sessions. This figure clearly illustrates the suppression of PLMS with pramipexole in every patient.
Number and index of PLMS and PLMW for 10 RLS patients in the four conditions (mean ± standard deviation)
Figure 2. Individual data for periodic leg movements during sleep (PLMS) in 10 patients with restless legs syndrome studied in four overnight recording conditions: baseline (B), withdrawal (W), placebo (Pl), and pramipexole (Pr). For each patient there is a drastic reduction in the number of PLMS with pramipexole.
Clinical observations.
Patients were seen every 2 weeks throughout the study. Nine of the 10 patients in this study reported a complete disappearance of RLS symptoms with pramipexole, 5 at a dosage of 0.375 mg/d and 4 at a dosage of 0.75 mg/d. The 10th patient reported a major improvement of symptoms but the persistence of some degree of leg discomfort and restlessness. The therapeutic effect was already present at 0.375 mg/d in this patient, who reported little additional improvement by increasing dosage. As mentioned previously, before entering the study eight patients had been using other therapies for RLS (four clonazepam, three levodopa, and one pergolide). They all rated the effect of pramipexole to be superior to the previous treatment.
Nine patients reported gastrointestinal side effects, including nausea, constipation, and loss of appetite with pramipexole. Four patients reported dizziness, and three reported daytime fatigue at pramipexole dosages of 0.375 or 0.75 mg/d. These side effects were mild and usually disappeared within 1 week after initiation of treatment or dosage increase. Persistent nausea or daytime fatigue appeared in two pramipexole patients at the 1.5 mg/d dosage; these patients returned to the 0.75 mg/d dosage. None of the patients dropped out of the study because of side effects.
Discussion.
Effect of pramipexole on leg discomfort at home. Results of the questionnaires showed that leg restlessness is worse in the evening, at bedtime, or during the night compared with the daytime. This is not surprising because the increase in severity of restlessness at night is a major feature of RLS and is used as a criterion to diagnose this condition. The worsening of symptoms at night is thought to be related to a circadian factor. A recent study of RLS patients during sleep deprivation suggests that RLS manifestations have a circadian periodicity with an acrophase occurring early during the night.29
Pramipexole had a major impact on diurnal and nocturnal symptoms of RLS as subjectively assessed by home questionnaires. These questionnaires showed a complete suppression of leg restlessness in the daytime, in the evening, at bedtime, and during the night in 9 of 10 patients. The last patient gave a high score of leg restlessness in each condition (baseline, placebo, withdrawal, pramipexole) in spite of reporting an improvement of symptoms at the time of the clinical evaluation and a suppression of PLMS during polysomnographic recording with pramipexole. A possible explanation for this discrepancy would be that this patient also experienced other musculoskeletal pain or discomfort independent of RLS and was therefore nonresponsive to pramipexole. In a previous study,17 an improvement of 38% in leg restlessness was seen at bedtime in RLS patients treated with levodopa under blinded conditions compared with 84% with pramipexole in the present study. These results suggest that pramipexole is more potent than levodopa in alleviating the symptoms of RLS.
Effect of pramipexole on motor manifestations in the sleep laboratory.
Pramipexole had a major effect on PLMS and PLMW. Benzodiazepines,10-12 levodopa,16,17 bromocriptine,22 and pergolide23-25 have also been reported to decrease the PLMS index. However, pramipexole is the first treatment that lowers the PLMS index to a normal value (below 5). Dopaminergic agents were also found to be effective to treat PLMS associated with other sleep disorders, such as narcolepsy,30 or to treat uremic patients affected with RLS.31 Results of the present study suggest that pramipexole may also be useful to treat RLS and PLMS associated with these conditions.
Pramipexole and nocturnal sleep architecture.
There was no effect of pramipexole on total sleep time, number of awakenings, or sleep efficiency in spite of a decrease in the number of PLMS as well as PLMS associated with arousals. Similar results were obtained in RLS patients treated with levodopa.17 It suggests that pramipexole, as other dopaminergic agents, does not have a sedative effect. On the contrary, it may have a stimulant effect, and it produced insomnia in some patients with PD.26 However, insomnia was not reported by any patient in the present study.
Pramipexole induced specific changes in sleep architecture, namely a delayed REM sleep latency and a decrease in REM sleep time and percentage of REM sleep. REM suppression has been reported with several antidepressant medications, including tricyclics and specific serotonin reuptake inhibitors.32,33 REM deprivation has been performed experimentally by awakening depressed patients during REM sleep, and this procedure has also produced an antidepressant effect.34 Therefore, it has been postulated that REM sleep suppression may be directly involved in the therapeutic action of antidepressants. Based on this hypothesis, pramipexole is expected to have a therapeutic effect in depression.33
Pramipexole in the treatment of RLS.
Therapeutic effects.
Based on clinical evaluations, home questionnaires, and polysomnographic recordings, pramipexole is the most potent therapeutic agent ever tested for treating RLS. The recommended dosage is between 0.375 and 0.75 mg/d. Indeed, 5 of 10 patients reported complete relief of RLS symptoms at 0.375 mg/d, and 9 of 10 patients at 0.75 mg/d. Little additional therapeutic gain was obtained by increasing the dose to 1.5 mg/d. However, the short duration of drug administration in the present study (1 month) did not allow the assessment of the safety or the efficacy of long-term administration of pramipexole.
Side effects.
Pramipexole was well tolerated by the patients at a dosage up to 0.75 mg/d, although several patients reported mild nausea during the first few days of treatment with 0.375 and 0.75 mg/d. This side effect may be due to the fast rate of increase in pramipexole dosage. Therefore, starting at a lower pramipexole dosage and slowly increasing it to prevent nausea is recommended. In a recent open clinical trial,35 pramipexole was effective in treating RLS at an average dose of 0.3 mg/d. In that study, the most common adverse effects were fatigue and stiffness. In the present study, daytime fatigue was seen in 3 of 10 patients, a prevalence similar to that reported in the open clinical trial (5 of 15 subjects). Although this fatigue was clinically important, it did not persist with dose reduction. Moreover, dose reduction did not compromise the therapeutic effect on RLS symptoms because, as already mentioned, little additional therapeutic gain was obtained by increasing the dose from 0.75 to 1.5 mg. There is no simple explanation for the presence of daytime fatigue in patients treated with pramipexole. Further studies should investigate the relationship between REM sleep suppression and daytime fatigue.
Dopaminergic hypothesis of RLS.
There are several pieces of evidence supporting the hypothesis that dopamine neurotransmission is involved in the physiopathology of RLS. Brain imagery using SPECT with iodine I-123 IBZM, a specific D2-receptor ligand, showed a decrease in D2-receptor binding sites in the striatum of patients with RLS.36,37 Pharmacologic evidence also supports the dopaminergic hypothesis of RLS because levodopa and D2-receptor agonists produce major therapeutic effects in RLS. Other studies have suggested that iron may be involved in the physiopathology of RLS. Several elderly RLS patients had low ferritin levels and benefited from iron therapy.38 A possible mechanism of action for iron in RLS is through its action on dopaminergic transmission. It has been shown that the D2 receptor is an iron-containing protein, and therefore iron deficiency may be associated with a hypofunction of this receptor.39 Results of the present study not only support the dopaminergic hypothesis, but the therapeutic effects of pramipexole on both subjective and objective measures of RLS suggest that the D3-receptor subtype of the D2-receptor family may be specifically involved in the physiopathology of this condition.
Acknowledgments
Supported by a grant from Pharmacia and Upjohn Inc.
Footnotes
-
See also pages 907, 932, 944, 1060, and 1064
- Received August 5, 1998.
- Accepted November 14, 1998.
References
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