Treatment of Restless Legs Syndrome With the Hypocretin Antagonist Suvorexant

Restless legs syndrome/Willis-Ekbom disease (RLS/WED) is a common neurological disorder characterized by the presence of an urge to move the legs, usually accompanied by dysesthesias1. It is estimated that approx. 60-75% of the patients experience these symptoms just at bedtime and its main consequence is insomnia. RLS is not only a common differential diagnosis with Primary Insomnia, but independently of this it is also one of the most common sleep disorders. In Western countries the prevalence for the more severe forms is approximately 2-3% of the general adult population.

Over the last years, dopamine agonists (DAs) have been widely used for RLS/WED. However, there is growing concern about the long-term consequences of DAs, such as dopaminergic augmentation. This complication consists of an overall increase in symptom severity, with symptoms starting earlier in the afternoon and expanding to previously unaffected parts of the body. If not stopped, augmentation can develop into a serious complication, as it will eventually progress and can lead to discontinuation of treatment. Existing studies show that after a treatment period of approximately 10 years, which is the amount of time that has elapsed since the first DA agonists were approved, the prevalence of augmentation nears 50%. But since RLS is a chronic disease in many patients, it is likely that with longer treatment times the risk of augmentation will increase even further. In light of this, there is a clinical need for treatment alternatives to dopaminergic drugs. Furthermore, a recent consensus paper by three RLS expert organizations recommends treatment begin with drugs other than dopaminergic agonists.

The pathophysiology of RLS/WED is not yet clear, but a number of findings link it to iron metabolism and to a mild dopaminergic dysfunction. Furthermore, it is not even clear whether the dopaminergic dysfunction plays a causal role at all, a fact that adds additional concerns about the use of dopaminergics. Drugs with non-dopaminergic mechanisms of action that have shown therapeutic efficacy for RLS/WED are alpha-2 delta ligands (pregabalin, gabapentin), opiates, benzodiazepines or clonidine. The only common mechanism through which these different agents might improve RLS symptoms is probably reduction of arousal. In fact, RLS even when moderate profoundly disturbs sleep, reducing sleep times to 5-6 hours or less. Patients report some daytime problems with alertness and cognitive clarity, but despite this reduction in sleep times untreated patients do not describe such profound episodes of sleepiness that occur for normal subjects maintained on such restricted sleep schedules. There is apparently some alerting mechanism partially compensating for the sleep loss. Such-hyperarousal-resembles the one found in Primary Insomnia. Indeed, RLS patients treated with dopaminergics over long periods frequently exhibit poor sleep despite the improvement of sensory and motor symptoms.

Increased glutamatergic activity has been discussed as one of the potential mechanisms leading to increased arousal in RLS. However, it is possible that the hypocretin system may also play a role in causing RLS-related hyperarousal. Hypocretins are well known to play a key role in the central regulation of both motor control and arousal. Two main studies have examined hypocretin levels in RLS patients. A first small study found increased evening hypocretin-1 levels in previously untreated patients with early onset RLS when compared to controls, but not in those treated. However, Stiasny-Kolster et al. were not able to replicate this finding, although the difference between both studies could be related to the treatment status and to the use of different extraction methods of cerebrospinal fluid (CSF). No evidence exists so far in the literature regarding the effect of hypocretin antagonist drugs in the treatment of RLS-related sensory and motor symptoms. However, unpublished data have shown non-significant improvements of periodic limb movements (PLMs) during treatment with almorexant.

This study hypothesizes that treatment of RLS symptoms with the hypocretin antagonist suvorexant might lead to an improvement of sleep as well as to an improvement of both dysesthesias and motor symptoms (PLMs).