Oral iron supplementation and the dopamine-inhibiting drug pramipexole are equally effective for treating patients with restless legs syndrome, and work along similar time frames, a South Korean research team has found.
While both iron and pramipexole are established treatments for restless legs syndrome (RLS), the new study (n = 30) was the first randomized trial to compare them head to head. The results, published online in the European Journal of Neurology (doi:10.1111/ene.12286), suggest that, because of the similar responses seen with both, the therapies might be combined in iron-deficient patients with RLS.
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While both iron and pramipexole are established treatments for restless legs syndrome (RLS), the new study was the first randomized trial to compare them head to head.
For their research, Dr. C.S. Lee of Seoul National University Bundang Hospital (SNUBH) and colleagues randomized RLS patients with a serum ferritin of 15-50 ng/mL to receive either pramipexole, starting at 0.25 mg daily and titrated to up to 0.75 mg, or ferrous sulfate 325 mg twice daily. Subjects and investigators were not blinded to treatment allocation.
Subjects in both groups were statistically similar in terms of age, sex (all but one were women), disease severity, and serum ferritin levels at baseline. In the pramipexole group, four patients dropped out because of adverse events, mostly gastrointestinal complaints; in the iron group, three were lost because of perceived lack of treatment effect or inability to meet appointments.
At 2, 4, 8, and 12 weeks, subjects were assessed using the international restless legs syndrome (IRLS) study group disease severity scale, and also evaluated using published depression and sleep quality scores.
Dr. Lee and colleagues found that at 12 weeks, disease severity scores were similarly reduced from baseline in both groups (iron: –9.1, plus or minus 7.07; P less than .001; pramipexole: –8.7, plus or minus 8.31; P = .001). Changes in scores from baseline were also similar between the two groups at each visit, suggesting that both treatments worked along similar time frames, a finding that the researchers said was unexpected. The percentage of patients whose IRLS score decreased by 50% or more during the study period was the same for both groups: 46.7%.
The study attempted in part to answer the question of which treatment – iron or pramipexole – should be tried first in this patient group. The researchers noted that iron deficiency is not always seen in RLS patients, suggesting that low iron alone cannot explain RLS, and that iron supplementation is likely not sufficient to control symptoms in all RLS patients with low iron.
Still, iron treatment is generally the first line in clinical practice, with supplementation lasting 3 months after iron levels return to normal, then stopped. Pramipexole tends to be used for longer periods; long-term use of pramipexole has been associated with tolerance and augmentation, a phenomenon in which symptoms start appearing earlier in the day (Sleep Med. 2004;5:9-14).
"To avoid long-term treatment and augmentation, oral iron supplementation is preferred to dopamine agonists in RLS patients with iron deficiency, but considering the moderate response rate to oral iron alone, a dopamine agonist or other treatment could be added in selected RLS patients with a low-normal serum ferritin," the researchers wrote in their analysis.
While additional studies are needed to corroborate the results, Dr. Lee and colleagues wrote, "the treatment guideline that RLS patients with iron deficiency can be treated by iron supplementation alone may need to be revised."
The investigators noted as weaknesses of their study its small size, lack of a placebo control arm, and nonblinded design.
The study was funded by a grant from the SNUBH Research Fund, and none of its authors declared conflicts of interest.