A Randomized, Placebo‐Controlled Crossover Study with Dipyridamole for Restless Legs Syndrome

Abstract

A BS TRACT: Background: New pharmacological targets are needed for restless legs syndrome. Preclinical data suggest that a hypoadenosinergic state plays an important pathogenetic role. Objective: The objective of this study was to determine whether inhibitors of equilibrative nucleoside transporters, for example, dipyridamole, could provide effective symptomatic treatment. Methods: A 2-week double-blind, placebo-controlled crossover study assessed the efficacy of dipyridamole (possible up-titration to 300 mg) in untreated patients with idiopathic restless legs syndrome. Multiple suggested immobilization tests and polysomnography were performed after each treatment phase. Severity was assessed weekly using the International Restless Legs Rating Scale, Clinical Global Impression, and the Medical Outcomes Study Sleep scale. The primary end point was therapeutic response. Results: Twenty-eight of 29 patients recruited were included. International Restless Legs Rating Scale scores improved from a mean AE standard deviation of 24.1 AE 3.1 at baseline to 11.1 AE 2.3 at the end of week 2, versus 23.7 AE 3.4 to 18.7 AE 3.2 under placebo (P < 0.001). Clinical Global Impression, Medical Outcomes StudySleep, and Multiple Suggested Immobilization Test scores all improved (P < 0.001). The mean effective dose of dipyridamole was 217.8 AE 33.1 mg/d. Sleep variables improved. The mean periodic leg movement index at the end of treatment with dipyridamole was 8.2 AE 3.5 versus. 28.1 AE 6.7 under placebo. Side effects (dipyridamole vs placebo) included abdominal distension (18% vs. 7%), dizziness (10.7% vs 7.1%), diarrhea, and asthenia (each 7.1% vs 3.6%). Conclusions: Dipyridamole has significant therapeutic effects on both sensory and motor symptoms of restless legs syndrome and on sleep. Our findings confirm the efficacy of dipyridamole in restless legs syndrome predicted from preclinical studies and support a key role of adenosine in restless legs syndrome.

Brain Iron Deficiency Changes the Stoichiometry of Adenosine Receptor Subtypes in Cortico-Striatal Terminals: Implications for Restless Legs Syndrome

“…In addition, increasing the extracellular levels of adenosine by application of dipyridamole, an inhibitor of equilibrative nucleoside transporters ENT1 and ENT2, inhibited basal and optogenetically-induced glutamate release by cortico-striatal terminals from rats with BID and controls [ 21 ]. These preclinical results predicted a possible clinical role of dipyridamole in RLS, which we could confirm in two recent clinical studies [ 6 , 7 ]. However, the actual BID-induced change in the A 1 R/A 2A R stoichiometry in cortico-striatal terminals still needs to be demonstrated.…”

“…These neurochemical changes have not yet been reported in patients with RLS, which would further validate the rodent with BID as an animal model of RLS. The “adenosine hypothesis” of RLS, however, is supported by the efficacy of dipyridamole in treating RLS symptoms [ 6 , 7 ].…”

“…Utilization of the BID-rodent model of RLS could allow the identification of new neurochemical pathways and changes not previously reported in the human condition. Alterations in the adenosinergic system found in the BID rodent model [ 3 , 5 ] was an important new translational finding that led to a new potential treatment for RLS [ 6 , 7 ].…”

Functional and pharmacological role of the dopamine D4 receptor and its polymorphic variants

“…Using the optogenetic-microdialysis method, evidence was also obtained for the ability of the equilibrative nucleoside transporter dipyridamole, which increases the extracellular levels of adenosine, to significantly inhibit cortico-striatal glutamate in control rats and in rats with BID ( 113 ). The results of these experiments indicated a possible therapeutic effect of dipyridamole, which was recently demonstrated by two clinical studies, an open trial, and a randomized, placebo-controlled crossover study ( 114 , 115 ). These studies provided a new therapeutic approach for RLS and significantly validated the cortico-striatal glutamatergic terminals as targets for the treatment of RLS.…”

Adenosine, caffeine, and sleep–wake regulation: state of the science and perspectives

“…This evidence led to the recent hypothesis that pharmacologically increased extracellular adenosine concentrations may improve sensorimotor and sleep symptoms in RLS (Garcia‐Borreguero et al, 2018). Consistent with this idea, blockade of adenosine reuptake by dipyridamole, a non‐selective ENT1/ENT2 inhibitor clinically used as vasodilator and inhibitor of blood platelet aggregation, proved therapeutic efficacy in RLS by reducing periodic limb movements during sleep, shortening sleep latency, increasing sleep efficiency, and enhancing the duration and proportion of slow‐wave sleep (Garcia‐Borreguero et al, 2021).…”