SLEEP 2026 | Rethinking restless legs syndrome treatment: the shift beyond dopamine agonists

Over the last two years, a major change has occurred in the field of treatment of RLS. Namely, the American Academy of Sleep Medicine has finally recognized that the first-line option should be reconsidered. The first-line treatment option should be reconsidered. Until then, the official policy was that new patients or patients, previously untreated patients, should be treated first with a dopamine agonist. There were a few years where they put at the same level dopamine agonist with gabapentinoid drugs. However, the problem of the dopamine agonist is that over time, they are going to lead to a complication called dopaminergic augmentation, that is an increase in symptom severity that is usually long-lasting, leads very frequently to treatment discontinuation, and worsens the quality of life of patients. That has been gradually recognized by the experts in the field. And finally, two years ago, the decision was taken that dopamine agonists should be, whenever possible, postponed. I wouldn’t say avoid it. If possible, avoid it. But in general, postponed. The first-line option should be a non-dopaminergic one. Okay, what do we have if we are not going to use the dopamine agonist? The alternative is going to be, well, in the United States you have one non-dopaminergic drug that is approved, and this is gabapentin enacarbil. But in general, just to group the entire family of drugs, we call them gabapentinoids. These are drugs that exert their effects by reducing glutamatergic function. The assumption is that in RLS some circuits, some neural circuits, particularly the corticostriatal pathways, which are glutamatergic, are hyperfunctioning, so the effect of gabapentinoids, whether pregabalin, gabapentin, or gabapentin enacarbil, is going to be to reduce the function, to diminish the hyperglutamatergic tone. These drugs have been shown in several clinical trials to be, over the short and over the long term, as effective as the dopamine agonists are, with the advantage that they do not cause augmentation. However, what is their downside? Their downside is that the rate of side effects can be, I would say, slightly higher. And also, there is another problem that once a patient has started a long-term treatment with a dopaminergic agent, the longer the patient has been on that dopaminergic agent, the less the patient will respond to a gabapentinoid, that has also been shown over the last years. So if you use them, use them as a first-line treatment before anything else is being used, because that’s the time point at which they are going to be most effective. However, there are some few problems that have been known over the last years, these drugs can have some short-term side effects, but over the long term, there are some reports, some prospective epidemiological reports that show that the rate of incidental dementia can be increased. The relative risk of incidental dementia following a treatment with a gabapentinoid is 1.4, approximately 1.4. That means compared to the same population, but those that are not being treated with gabapentinoids, there is a 40% increase in the rate of incidental dementia. What does it mean? These patients meet criteria for dementia, but we do not know whether this dementia is reversible or not. In most cases, it is. In most cases, it is. However, there is some speculation on whether there is a portion of the cases where what a gabapentinoid might be doing is accelerating other concurrent problems leading to dementia. For example, the rate of phosphorylation, this all comes from animal studies, the rate of phosphorylation of tau protein is increased. Also, the expression of hippocampal SIRT1 protein, which is one of the factors involved in the pathogenesis of dementia, is also increased. These drugs might also interfere with synaptogenesis, with the formation of new synapses. So there are reasons to be careful. So what do we recommend? We recommend doing a baseline evaluation of cognitive function. The risk of dementia is highest in those patients where the renal function is working worse. So periodically, systematically, check serum creatinine and also check GFR, the renal function, basically. And this is most likely going to be impaired in the elderly patients. So be careful with the total dose.

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