Nonergotderived dopamine agonists

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There are three newer fully-synthetic dopamine agonists that are not derived from ergot. The three drugs include ropinirole, pramipexole, and rotigotine. As of July 2011, rotigotine is not approved by the FDA for use for RLS in the USA. These nonergot agents are not associated with valvular heart disease but have been associated with impulse control disorders including pathological gambling, compulsive overeating, hypersexuality, and pyschosis. There is increasing recognition that patients treated with these agents should be monitored for impulse control disorders.

Ropinirole acts as a dopamine agonist primarily on the D3 as well as D2 & D4 receptors. It was originally studied in the early 1990s for Parkinson's Disease and later found to be beneficial for RLS. Ondo studied 16 RLS patients in an open-label trial of ropinirole. Three patients discontinued ropinirole use. Of the remaining 13 patients, the average duration of use was 3.9 months and there was a 58.7% improvement in symptoms (Ondo W, 1999). Further studies reinforced the safety and efficacy of ropinirole in RLS. The TREAT RLS 1 study (Therapy with ropinirole; efficacy and tolerability in RLS 1) was a randomized, double-blinded, placebo-controlled trial of 12 weeks duration. 146 subjects were randomized to the ropinirole group and 138 to the placebo group. The key endpoint was the IRLS severity score which showed significant improvement in the ropinirole group over the placebo group at week 12 (p=0.0036). The researchers concluded that ropinirole improves RLS compared with placebo and was generally well-tolerated (Trenkwalder C et al. 2004). More recent similar studies from the USA and Canada confirm the efficacy and safety of ropinirole, including long-term duration in the Canadian study. In the USA study, Bogan and colleagues studied 331 subjects in a multicenter, double-blinded, placebo-controlled, flexible dose trial of 12 weeks duration. The primary endpoint was the IRLS score at week 12 which showed a significant improvement in the ropinirole group (p<0.001). In addition, the treatment group showed improvements in subjective measures of sleep disturbance and quantity and quality of life scores also improve. The authors concluded that ropinirole improves RLS symptoms and was generally well-tolerated over a 12 week study period (Bogan RK et al. 2006). In the Canadian study, researchers studied the long-term efficacy (36 weeks) of ropinirole and also evaluated for the potential of symptom relapse after drug discontinuation. They identified 202 patients and found significantly fewer subjects relapsed in the ropinirole arm compared to placebo (32.6% versus 57.8%, p=0.0156). In addition, the time to relapse symptoms was longer in the ropinirole group and less patients withdrew from lack of efficacy in that group. The authors concluded that ropinirole was highly efficacious and well-tolerated over a 36 week period (Montplaisir J et al. 2006). In 2008, Allen and colleagues reviewed RLS age-of-onset and the response to treatment. They observed no relationship between the RLS symptoms age-of-onset and baseline IRLS score, and between dose administered at week 12 and age-of-onset. The authors concluded that ropinirole provides effective RLS symptom relief that is not affected by age of symptom onset (Allen RP, Ritchie SY, 2008). In 2009, a large meta-analysis was conducted to evaluate the effect of ropinirole versus placebo on sleep outcomes as measured by the Medical Outcomes Study (MOS) sleep scale. The validated MOS sleep scale is a 12 question scale which evaluates sleep disturbance, sleep adequacy, snoring, somnolence, quantity of sleep, and other measures. In this review, the authors found that ropinirole improved sleep quality and decreased daytime somnolence in patients with primary RLS (Hansen RA, et al., 2009). Finally, researchers assessed the efficacy of ropinirole on depressive symptoms and RLS. In a multicenter, randomized, double-blinded, placebo-controlled trial, 231 patients with moderate to severe primary RLS and at least mild depression were studied. Ropinirole versus placebo was given for 12 weeks with measurements obtained at baseline and 12 weeks for the Montgomery-Asberg Depression Rating Scale, the Hamilton Scale for Depression and Beck Depression Inventory-II score, and the Medical Outcomes Study sleep scale. There were significant improvements in the Montgomery and Hamilton scores as well as 3 of the 4 domains of the MOS sleep scale. The authors concluded that in patients with RLS and mild to moderate depression, appropriate therapy for RLS should first be tried and antidepressant medication may be needed later if the depression symptoms still persist (Benes H et al., 2011). In summary, ropinirole is a newer nonergot-derived dopamine agonist with a particular affinity for the D3 dopamine receptors. It has been shown to be beneficial in RLS symptom improvement both short and long-term with improvement in daytime somnolence and quality of life indicators.

Pramipexole is a nonergot-derived dopamine agonist that acts on the D3 as well as D2 and D4 receptors. One of the earliest RLS studies was conducted by Lin at the Mayo Clinic in 1998. In that research, 16 patients were studied who had failed other dopaminergic therapies for symptomatic RLS. An open-label trial showed that after 2 to 3 months usage, there was clinically significant improvements in nocturnal leg restlessness and involuntary leg movements. The authors proposed that pramipexole was an effective therapy for the treatment of RLS (Lin SC et al., 1998). Following that encouraging initial report, a small randomized trial was conducted in Quebec. Researchers studied 10 RLS subjects with PSG and RLS symptom questionnaire using a double-blinded crossover study. They found a significant reduction in PLMs and RLS symptoms of bedtime/nocturnal leg discomfort (Montplaisir J et al., 1999). A larger randomized trial from Finland evaluated the efficacy and safety of pramipexole in 2006. In this study (the PRELUDE study), 109 patients with moderate to severe RLS (based on the IRSS severity score) were randomized in a 3 week, double-blinded, placebo-controlled, dose-finding study. PSG measures and IRLS severity scores were assessed. At all doses, the PLM index was reduced and IRLS severity scores reduced. The authors concluded that pramipexole was an effective and safe therapy for treatment of both the objective (PSG measures) and subjective (IRLS severity) aspects of RLS (Partinen M et al., 2006) In a long-term 52 week open-label study, Japanese researchers found that pramipexole was both effective and safe (with no RLS augmentation), especially in patients with an IRLS score less than 20 (Inoue Y, et al., 2010). In a more recent, multicenter trial, pramipexole was evaluated for efficacy and augmentation problems over a 6 month period. This was a 6 month, randomized, double-blinded, placebo-controlled trial in which 321 patients were recruited. Primary endpoint for efficacy was the change in the IRLS severity score. In addition, patients maintained a symptom diary and cases that met predefined criteria for suspected augmentation were reviewed by a blinded panel. The study showed that pramipexole was significantly more effective than placebo in improvements of IRLS severity (p=0.0077). Over 6 months, the incidence of confirmed augmentation was 9.2% in the pramipexole group versus 6.0% in placebo and the rate increased with treatment in the intervention group but not placebo. Overall, the authors felt that pramipexole was effective and safe but did suggest it should be studied over a longer duration for further assess augmentation issues (Hogl B, et al., 2011). More recent trials evaluating pramipexole has focused on comparison with other dopaminergic agonist. In a recent study by Manconi, pramipexole (mainly a D3 receptor agonist) was compared with bromocriptine (largely a D2 receptor agent) and researchers found that pramipexole was more effective than bromocriptine in reduction of PLMs and that while both drugs reduced RLS symptoms, the pramipexole group had greater symptom improvements (Manconi M et al., Neurology 2011). The same Italian group also did a recent comparison of pramipexole to ropinirole. Researchers found that both treatment groups improved RLS symptoms and reduced PLMs on PSG compared to the placebo group and that there was no significant differences between the pramipexole and ropinirole treatment arms (Manconi M et al. Mov Disorders 2011). In summary, pramipexole is a newer nonergot-derived dopamine agonist with preferential action on the D3 dopamine receptor site. It has been shown to be beneficial for both objective PSG PLM findings as well as subjective improvements in RLS clinical symptoms. It is generally well-tolerated although there may be an issue with augmentation long-term. Rotigotine is another newer nonergot-derived dopamine agonist. It is formulated as a once daily transdermal patch and approved to treat RLS in Europe but not FDA-approved for the USA. It appears to mainly work on the D2, D3, and D4 receptor sites. In one of the earliest pilot studies to show benefit for RLS patients, German researchers in 2004 evaluated 63 patients. In this randomized, multicentre, double-blind, parallel-group trial, 63 subjects were studied using the IRLS severity score as the primary endpoint. Researchers found a significant improvement in the treatment group and concluded that transdermal rotigotine was efficacious and well-tolerated (Stiasny-Kolster K et al., 2004). More recently in a multicenter, randomized, double-blind, placebo-controlled 6 month trial, 505 patients with moderate to severe RLS were placed on placebo or rotigotine with the primary endpoints being the IRLS severity score and the CGI-1 score. The treatment group had significantly improved IRLS and CFI-1 outcomes. There was an overall 27% incidence of skin reactions to the transdermal patch. Overall, the authors concluded that rotigotine significantly reduced the severity of RLS symptoms and that treatment effectiveness was maintained throughout the 6 month study period (Hening WA et al., 2010). Rotigotine was also recently assessed in an overnight PSG study evaluating objective PLM measurements. This study was a multicenter, randomized, double-blind, placebo-controlled trial that evaluated 67 subjects over a 4 week period. Baseline and 4 week PSG and subjective questionnaires (IRLS, CGI-1, MOS-S) were obtained. The authors found significant improvements in both the subjective questionnaires but also the objective PSG PLM data. The researchers concluded that rotigotine was effective and well tolerated in the 4 week treatment of both motor symptoms and subjective sleep disturbances caused by RLS (Oertel WH et al., 2010). Finally, in a long term follow-up study, rotigotine was shown to provide sustained effectiveness in treating moderate to severe RLS symptoms for up to 5 years and was generally well-tolerated (Oertel W et al., 2011).

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