Skip to content

Treating restless leg syndrome: the present and the future

  • by

Diego Garcia-Borreguero, MD, PhD, Sleep Research Institute, Madrid, Spain, shares an overview of the treatment landscape for restless leg syndrome (RLS). Currently, dopamine agonists are widely used for the treatment of RLS, including ropinirole, rotigotine, and pramipexole. However, pharmacological tolerance and dopamine augmentation frequently prevent their long-term use. Dr Garcia-Borreguero emphasizes the need for new therapeutic options in this space, highlighting several lines of research underway. Intravenous iron and Alpha-2-delta calcium channel ligands can be effective for RLS. Perampanel and dipyridamole are also promising non-dopaminergic agents in development. This interview took place at the European College of Neuropsychopharmacology congress 2021.

In most western countries the drugs that are approved for the treatment of aureleus are dopamine agonists these drugs are a pramipexo ropinirole and rotigotine uh and that applies to most of the western or the developed countries because the same thing occurs in in japan as well however uh in the united states and in japan uh there is an additional drug that is

Also approved for rls which is a it’s a derivative of gabapentin gabapentine in a kerbal it’s not exactly in there with it’s a pro drug of gabapentin okay um dopamine agonists are drugs that are very effective for or less over the short term however when you use them and we’re talking here about the a condition that usually lasts a oh it’s a lifelong disease in

Many patients in many many patients i would say at least in two of the patients so a being a long-lasting disorder i mean drugs that are effective over the first weeks or months or maybe years at most are not satisfying satisfying the the patient’s needs so that means they are good for the short term but over the long term pharmacological tolerance develops that

Means in other words the drug is no longer a producing the same effect when you see that when the physician sees that he she will have two two choices other just live with that it’s better said when the patient sees that but okay either you keep the dose and accept the situation as it is or you increase the dose if you increase those the likelihood of creating

The so-called dopaminergic augmentation is very high all dopaminergics produce augmentation normally the term augmentation is very it can be confusing because normally when we talk in medicine about documentation we are talking about augmenting the effects of the treatment that’s the way i know it at least here we should be talking dopaminergic augmentation of

Symptoms it’s not that the treatment becomes more potent no it’s that the symptoms become worse so it’s a kind of geotrogenic worsening of symptoms because of the dopaminergic agent that’s something that every dopaminergic agent shares in common uh and the none of the non-dopamineologic agents have it it’s exclusively specific for dopaminergics in dopaminergic

Augmentation is a real problem it’s a real problem because patients no longer respond to dopaminergics even more our group also found that during dopaminergic augmentation the response to non-domain analytics is also very low the response to gabapentin in a carbon is also very low so the only solution for these patients is opioids mild potency opiates are being

Used for that with all the problems that the opiates might have um so having said this as an introduction there is there are unmet needs in rls there are several lines of research in progress part of the problem in rls is that we do not have we do not have a very uh a good understanding of the pathophysiology of rls however new findings over that

Have been described over the last years are opening new new pathways first of all the um we know that in our lis uh patients with rls have problems in their iron storage the main storage of iron in the brain must be most people most doctors do not know that there is any iron in the brain but okay having said that i mean there is the main iron storage system

In the substantia which is an area linked to the basal ganglia that regulates movement regulates inform sensory information and it’s also one of the main iron storages in the brain and a number of studies have shown that whenever this whenever there is a reduction in the content of brain iron are less well developed based on that are new ways of making more

Iron accessible to the brain and saying it in a simple way that means intravenous iron has been has become more more common in the for the treatment of rls of course this is a kind of treatment that requires taking cautions i personally recommend neurologists to work together or to consult to lead or at least to to to to to do it together with them with a

Hematologist or an internist or at least with someone that has experience in the administration of iv iron but this is one of the ways of of improving the disorder iv iron would be one of the ways the other one is that we know that this brain iron deficiency in rls produces uh some problems in several neurotransmitters one of them is um glutamate patients

With rls are undergoing a hyper glutamatergic effect a state glutamate is overacting in particularly in the cortico stratal pathways and that leads to the symptoms this is the reason why alpha two delta ligands alpha two delta ligands is a way of of nominating of of calling a pregabalin in gabapentin so gabapentinoid drugs what they basically do is they

Reduce the glutamatergic function this is their main mechanism of action in rls and these drugs are are effective for release so that means pregabalin in in in gabapentin and also in the united states cover painting in a carpet okay uh the other another drug that might be useful although it requires far longer clinical development could be paramparan it’s a

Phi company it’s a trade name a parampanel is a drug it’s an ampa receptor antagonist and the study of our group also showed that it could be it reduced uh realistic symptoms as well and finally the main finding over the last years has been are that adenosine which is a neurotransmitter that normally antagonizes glutamate it it’s one of the main uh factors

Leading to sleepiness at night i mean uh during wake time there is usually an accumulation of uh adenosine in the intercellular space and that’s somehow designer that the sleep centers and take for initiating the sleep process okay um adenosine is low in in our release we also know that it has something why is it low it has something to do with the law with

The brain iron deficiency the brain iron deficiency at least in animal models leads to a down regulation of the adenosine a1 receptor and then that leads to low adenosine low adenosine would unleash or it would disinhibit glutamate and that would lead to the symptoms what does it mean in terms of clinical development for now what we know is that a drug that

Reduces wealth that increases intra intercellular um adenosine which is the pyridamole subtracted an old drug and anti-aggregate one of the effects it has is that it blocks the re-uptake of a in of adenosine and by doing that it increases inter cellular intercellular and adenosine and by doing that ultimately what it will do it will reduce glutamatergic

Function so there are a number of new drugs in the horizons and that these drugs might change in a few years the way rls is being treated you

Transcribed from video
Treating restless leg syndrome: the present and the future By VJNeurology