Medline ® Abstracts for References 23,69

BACKGROUND: Dopaminergic medications relieve symptoms of the restless legs syndrome (RLS) but have the potential to cause iatrogenic worsening (augmentation) of RLS with long-term treatment. Pregabalin may be an effective alternative.

METHODS: In this 52-week, randomized, double-blind trial, we assessed efficacy and augmentation in patients with RLS who were treated with pregabalin as compared with placebo and pramipexole. Patients were randomly assigned to receive 52 weeks of treatment with pregabalin at a dose of 300 mg per day or pramipexole at a dose of 0.25 mg or 0.5 mg per day or 12 weeks of placebo followed by 40 weeks of randomly assigned active treatment. The primary analyses involved a comparison of pregabalin and placebo over a period of 12 weeks with use of the International RLS (IRLS) Study Group Rating Scale (on which the score ranges from 0 to 40, with a higher score indicating more severe symptoms), the Clinical Global Impression of Improvement scale (which was used to assess the proportion of patients with symptoms that were "very much improved" or "much improved"), and a comparison of rates of augmentation with pregabalin and pramipexole over a period of 40 or 52 weeks of treatment.

RESULTS: A total of 719 participants received daily treatment, 182 with 300 mg of pregabalin, 178 with 0.25 mg of pramipexole, 180 with 0.5 mg of pramipexole, and 179 with placebo. Over a period of 12 weeks, the improvement (reduction) in mean scores on the IRLS scale was greater, by 4.5 points, among participants receiving pregabalin than among those receiving placebo (P<0.001), and the proportion of patients with symptoms that were very much improved or much improved was also greater with pregabalin than with placebo (71.4% vs. 46.8%, P<0.001). The rate of augmentation over a period of 40 or 52 weeks was significantly lower with pregabalin than with pramipexole at a dose of 0.5 mg (2.1% vs. 7.7%, P=0.001) but not at a dose of 0.25 mg (2.1% vs. 5.3%, P=0.08). There were six cases of suicidal ideation in the group receiving pregabalin, three in the group receiving 0.25 mg of pramipexole, and two in the group receiving 0.5 mg of pramipexole.

CONCLUSIONS: Pregabalin provided significantly improved treatment outcomes as compared with placebo, and augmentation rates were significantly lower with pregabalin than with 0.5 mg of pramipexole. (Funded by Pfizer; ClinicalTrials.gov number, NCT00806026.).

OBJECTIVES: The aim of the study was to prospectively examine all patients with a diagnosis of RLS consulting a sleep disorders clinic and to assess RLS severity and augmentation and their associations, including ferritin levels.

METHODS: Patients were stratified into patients with RLS as ancillary diagnosis, RLS sufferers without current augmentation and RLS sufferers with current augmentation. Work-up included RLS severity scales and blood biochemical variables including indices of iron metabolism.

RESULTS: In an 18-month period, 302 patients with RLS (183 women, 119 men; mean age, 59.1+/-13.7 years) were recruited. RLS was considered idiopathic in 291 patients (96.4%). Most patients (240, 79.5%) were RLS sufferers, whereas the remaining 62 (20.5%) had RLS as ancillary diagnosis. Nineteen out of 162 patients treated with dopaminergic agents (11.7%) had current augmentation. Almost one-third of all patients (31.1%) had ferritin levels<50microg/l. Patients with an ancillary diagnosis of RLS had higher ferritin levels than RLS sufferers without current augmentation. The lowest ferritin levels were present in RLS sufferers with current augmentation 132.8+/-98.0microg/l vs. 100.6+/-84.5microg/l vs. 55.8+/-43.6microg/l; p=0.002). Patients with augmentation did not differ from non-augmented patients regarding age, gender, RLS etiology, presence of previous augmentation, or any other documented comorbidity (p>0.05).

CONCLUSION: The severity spectrum of RLS in this clinical cohort ranged from the ancillary diagnosis of RLS to augmented RLS. There was an inverse correlation between RLS severity and ferritin levels. Patients with current augmentation had the lowest ferritin levels. Our data further strengthen a putative role of low iron stores as a potential aggravator of idiopathic RLS. Moreover, low ferritin might represent a potential biomarker of RLS augmentation under dopaminergic therapy.