Permax®Pergolide Helpful for Restless Legs Syndrome
April 28, 2004 — Pergolide is safe and effective for at least 12 months for the treatment of restless legs syndrome (RLS), according to the results of a randomized, prospective, longitudinal trial in the April 27 issue of Neurology.
"Previous studies have indicated the efficacy of pergolide in treating RLS," lead author Claudia Trenkwalder, MD, from Georg August University in Goettingen, Germany, says in a news release. "However, they generally included small numbers of patients or short durations of treatment, limiting conclusions regarding the clinical use of pergolide therapy."
From September 1998 through July 2000, investigators in the Pergolide European Australian RLS (PEARLS) study enrolled 100 patients with RLS, aged 18 to 75 years, from 17 medical centers in Australia, Belgium, Finland, Germany, Italy, Netherlands, and Spain. The first phase of this study was a double-blind, parallel, randomized six-week comparison of pergolide vs. placebo, followed by a long-term extension in which responders to either pergolide or placebo continued to receive blinded medication, and nonresponders received open-label pergolide for up to 12 months of total study treatment.
Before treatment, all patients received domperidone for 10 to 14 days to maintain investigator blinding, which could be negated by pergolide-induced nausea. The pergolide dose was 0.25 mg to 0.75 mg in the evening. Primary efficacy measures were sleep efficiency and periodic limb movements during sleep (PLMS), and the validated International RLS Scale was used to grade RLS severity.
In the double-blind phase, pergolide reduced the PLMS arousal index compared with placebo (P = .004) and improved RLS severity scores (P < .001) and reported quality of sleep (P < .001), but it did not improve sleep efficiency.
After 12 months of treatment in the extension phase, patients initially randomized to pergolide maintained improvements. Patients initially randomized to placebo but then switched to open-label pergolide had dramatic improvements in the PLMS arousal index. Nausea and headache were more common in patients treated with pergolide than those treated with placebo.
Study limitations include possible bias introduced by the study design.
"Our study demonstrates that pergolide substantially improves PLMS measures and subjective sleep disturbance associated with RLS," Dr. Trenkwalder says. "We are also satisfied by how well-tolerated the low-dose pergolide treatment was, and that its efficacy was maintained over the long term."
Eli Lilly and Co. sponsored this study and employs two of its authors.
Study Highlights
• 100 patients aged 18 to 75 years from 17 centers in 7 countries were randomized to pergolide (n = 47) or placebo (n = 53).
• Inclusion criteria were clinical diagnosis of RLS by International RLS Study group criteria, sleep disturbance for at least 3 months, PLMS index of more than 5 arousals per hour of total sleep time, and sleep efficiency (SE) of less than 85%.
• Exclusion criteria included anemia, sleep apnea, and primary sleep disorders.
• Use of medications known to improve RLS was not permitted during the study.
• Phase 1 was a double-blind, parallel, 6-week comparison of pergolide with identical-looking placebo after titration in increments of 0.25 mg per day to a maximum dose of 0.75 mg per day.
• Phase 2 (conducted to 12 months) consisted of responders from phase 1 (receiving either drug or placebo) continuing on designated treatment, while nonresponders had their medication down-titrated and were then allowed open-label treatment with pergolide, with titration to a maximum dose of 1.5 mg per day.
• Up to 0.75 mg was given in a single daily evening dose. Additional doses were given separately.
• Primary outcomes were PLMS arousal index and SE assessed by polysomnography (PSG). Secondary outcomes were total sleep time (TST) and PLM index (number of PLM/hour in bed), International RLS Scale for severity (IRLS), and the Clinical Global Impressions (CGI) and Patient Global Impressions (PGI) scales.
• Safety monitoring included assessment of compliance, adverse events, physical examination, and laboratory tests.
• Intent-to-treat analysis was used. Data from the blinded and open-label phases were pooled.
• The majority of patients were women, with mean age of 56.2 years
• 40.4% of the pergolide group and 52.8% of the placebo group had received no previous treatment for RLS. The most frequently used previous medications were benzodiazepines.
• 68.1% of pergolide patients vs. 15.1% of placebo patients in phase 1 were considered treatment responders.
• The mean pergolide dose at the end of phase 1 was 0.40 ± 0.18 mg per day. Mean pergolide dose was 0.48 ± 0.2 mg per day at 6 months and 0.52 ± 0.22 mg per day in the double-blind continuation group.
• In phase 1, pergolide significantly reduced PLMS arousal index score compared with placebo (P = .004), but SE did not significantly improve. SE improved by a mean of 11.3% in the pergolide group compared with 6.1% in the placebo group (P = .196).
• Pergolide was associated with a significant improvement in the PLM index score (P < .001), the IRLS score (P < .001), and the CGI (P < .001) and PGI improvement scales (P < .001) compared with placebo.
• Patient ratings of sleep quality as documented in diaries improved significantly for pergolide compared with placebo (P < .001).
• In the open-label group, dose was 0.68 mg ± 0.55 mg per day at 6 months and 0.72 ± 0.42 mg per day at 12 months in the nonresponders who were receiving pergolide in phase 1. In the initial placebo patients, dose was 0.55 ± 0.31 mg per day at 6 months and 0.67 ± 0.31 mg per day at 12 months.
• Improvements continued in the pergolide treatment groups in phase 2 and were maintained at 12 months.
• Patients switched from placebo to open-label pergolide in phase 2 showed marked improvement in PLM index, PGI improvement scale, CGI scale, and IRLS scores, which were maintained at 12 months.
• Change in TST did not differ between groups.
• 99 patients were analyzed for safety outcomes. 67.4% of pergolide patients and 54.7% of placebo patients reported adverse effects, but the difference was not significant.
• Nausea and headache were significantly more frequent in the pergolide group than in the placebo group.
Source: Neurology. 2004;62:1391-1397
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History
Eli Lilly and Company now enters its 126th year of business. The global, research-based company was founded in May 1876 by Colonel Eli Lilly in Indianapolis, Ind., in the Midwestern section of the United States. A 38-year-old pharmaceutical chemist and a veteran of the U.S. Civil War, Colonel Lilly was frustrated by the poorly prepared, often ineffective medicines of his day. Consequently, he made these commitments to himself and to society:
• He would found a company that manufactured pharmaceutical products of the highest possible quality.
• His company would develop only medicines that would be dispensed at the suggestion of physicians rather than by eloquent sideshow hucksters.
• Lilly pharmaceuticals would be based on the best science of the day.
Although his business flourished, Colonel Lilly wasnt satisfied with the traditional methods of testing the quality of his products. In 1886, he hired a young chemist to function as a full-time scientist, using and improving upon the newest techniques for quality evaluation. Together, they laid the foundation for the Lilly tradition: a dedication that first concentrated on the quality of existing products and later expanded to include the discovery and development of new and better pharmaceuticals.
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