Circadian Pattern in Restless Legs Syndrome: Implications for Treatment Posology

The symptoms of restless legs syndrome (RLS) follow a circadian pattern, as inducated in the current RLS diagnostic criteria. Indeed, subjects with mild-to-moderate RLS suffer or not from RLS symptoms depending on the time of day, resembling an above-threshold state periodically followed by a below-threshold state. Although the circadian clock is crucial in the clinical features of RLS, research assessing the ultimate drivers of circadian rhythmicity is still very limited. In the present review, we show current evidence on circadian variations of neurotransmitters involved in the pathophysiology of RLS (systemic iron metabolism, brain iron homeostasis, adenosine, dopamine, glutamate, and endogenous opioids). Secondly, an overview of available therapies for RLS is presented, including information on current recommendations for symptomatic treatments in RLS. We discuss the importance of further research into the circadian oscillations that occur in RLS, so that they can be managed, and a protective below-threshold state can be established on an individualized basis. In addition, we also discuss the current dosing of the medications prescribed in RLS symptomatic treatments, and how circadian factors should be considered to better adjust dosing on an individualized basis and increase the therapeutic benefit.