New Treatment Option for Restless Legs?

Erik Greb

July 20, 2021

The antiplatelet medication dipyridamole reduces motor and sensory symptoms of restless legs syndrome (RLS) and improves sleep duration for treatment-naive patients, results of a small, randomized, placebo-controlled trial show.

After 2 weeks of treatment, scores on the International Restless Legs Rating Scale (IRLS) decreased by 13 points for patients who received dipyridamole, compared with 5 points among those who received placebo.

Dr Diego García-Borreguero

"Dipyridamole, a drug that acts exclusively upon adenosinergic pathways, with no known direct dopaminergic or glutamatergic effects, is therapeutically effective and implicates adenosinergic pathways in the pathophysiology of the disorder," Diego García-Borreguero, MD, PhD, director of the Sleep Research Institute, Madrid, Spain, told Medscape Medical News.

"It seems particularly relevant to restate that these were treatment-naive patients, since it is well possible that patients who have been exposed to long-term treatment with dopamine agonists or who suffer from augmentation do not respond that well," he added.

The findings were published online June 17 in Movement Disorders.

Standard Treatment Falls Short

Dopamine agonists such as pramipexole and ropinirole are effective for the short-term treatment of RLS. However, if administered for a longer period, these medications often increase symptom severity ("augmentation").

Once this occurs, symptoms no longer respond well to other similar medications, suggesting the need for drugs with different mechanisms of action. Previous research shows that after a treatment period of 10 years, the prevalence of augmentation is close to 50%.

In an open-label study in 2018, researchers treated patients with RLS with dipyridamole, a nonselective equilibrative nucleoside transporter (ENT) antagonist. After 8 weeks of treatment, RLS dysesthesias, periodic limb movements (PLMs), and sleep significantly improved.

The investigators conducted the current trial to evaluate the efficacy of dipyridamole in RLS. Eligible patients met the 2014 International Restless Legs Syndrome Study Group criteria for idiopathic RLS. Their IRLS score was >20 at baseline, and they experienced symptoms at least three times per week. No patients had received dipyridamole previously.

The investigators randomly assigned patients in equal groups to one of two study arms. Each study arm received treatment for two consecutive 2-week periods. One group received dipyridamole first, then placebo. The other group received the treatments in the reverse order.

A 1-week washout period preceded each treatment period. During a titration stage, participants received 100 mg/d for 3 days; the dosage was then increased to 200 mg/d.

Participants underwent assessments every 2 weeks. The primary endpoint was IRLS score. The secondary endpoints were scores on the Clinical Global Impression-S (CGI) scale, the Medical Outcomes Sleep (MOS) scale, the Multiple Suggested Immobilization Test (m-SIT), and polysomnography (PSG). The investigators also assessed side effects weekly.

Increased Total Sleep Time

Of 29 patients who were screened, 28 were included in the study. The mean age of the participants was 60 years. Approximately 65% of participants were women, and 100% were White. There were no significant differences in IRLS and CGI scores between the groups at baseline.

The mean decrease in IRLS score was 13 points with dipyridamole and 5 points with placebo (P < .001). The mean decrease in CGI score was 1.9 points with dipyridamole and 0.4 points with placebo (P < .001). Improvements on the subjective and motor dysfunction scales of m-SIT also were significantly greater with dipyridamole than with placebo (P < .001).

Sleep adequacy and sleep quantity, as measured by MOS, improved for patients who received dipyridamole, compared with those given placebo (P < .001 for both). However, there was no difference in daytime sleepiness between groups.

PSG indicated that sleep latency was 7.2 min shorter (P = .007) with dipyridamole than with placebo. Sleep efficiency was 82.5% with dipyridamole and 77.1% with placebo (P = .003). Dipyridamole also reduced the frequency of PLMs of sleep and PLMs associated with arousal (P < 0.001), compared with placebo.

At the end of the treatment period, the mean dose was 218 mg/d for dipyridamole and 250 mg/d for placebo. The most common side effects of dipyridamole treatment were abdominal distension (18% vs 7%), dizziness (10.7% vs 7.1%), diarrhea (7.1% vs 3.6%), and asthenia (7.1% vs 3.6%). No participants discontinued the study because of side effects.

Although the study's primary endpoints were subjective, the secondary endpoints (sleep study and immobilization test results) were objective. The results indicated dipyridamole's therapeutic efficacy across all the endpoints, said García-Borreguero.

Dopamine agonists generally improve PLMs and RLS symptoms during sleep. This class of drugs usually increases total sleep time but not slow-wave sleep. "In contrast, dipyridamole does lengthen total sleep time and particularly increases slow-wave sleep," said García-Borreguero.

Brain iron deficiency, which is considered a major pathophysiologic mechanism in the development of RLS, leads to a downregulation of A1 receptors. Although A1 agonists would seem to be appropriate for treating RLS, this class of drugs is particularly cardiotoxic.

"We currently are looking for more potent ENT inhibitors and also for drugs that pass the blood-brain barrier more effectively than dipyridamole," said García-Borreguero.

"Very Impressive" Data

Commenting on the study for Medscape Medical News, John Winkelman, MD, PhD, chief of the Sleep Disorders Clinical Research Program at Massachusetts General Hospital and professor of psychiatry, Harvard Medical School, Boston, Massachusetts, said more treatment options for RLS are needed.

Dr John Winkelman

Although treatment options are better than they were 25 years ago, they remain imperfect, he said, citing the risk for augmentation associated with dopamine agonists.

"The data from this study are very impressive," said Winkelman. The researchers used the standard endpoints that the US Food and Drug Administration uses to evaluate drugs for RLS. In addition, the investigators used PSG and the m-SIT, which "has good ecological validity," said Winkelman.

The study's weaknesses include its small sample size and short duration. Other important limitations include the fact that participants did not have symptom augmentation and had not been exposed to dopamine agents, said Winkelman.

"It doesn't cover all of the patients that we see in clinical practice, and it doesn't cover the most challenging ones," he added. Nevertheless, the study provides a strong proof of concept.

In addition, the trial "has immediate clinical implications," Winkelman said. For patients without augmentation who have not responded to or cannot tolerate existing therapies and for whom iron therapy is not appropriate, neurologists might consider dipyridamole before offering opioids, he added.

"It's exciting to have something new, given the position we're in," Winkelman concluded.

The study was conducted without outside funding. García-Borreguero and Winkelman have disclosed no relevant financial relationships.

Mov Disord. Published online June 17, 2021. Full text

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