Reviewed by Sahil Chopra, MD, and Stacey Gunn, MD.

Research by Savit Malhotra and Theresa Do.

Introduction

You might be wondering after reading our most recent article on dopaminergic medications: if dopaminergic agents are no longer the first line of treatments, then what kind of treatments are utilized instead? The management of Restless Legs Syndrome (RLS) has evolved significantly over the years, moving away from a primary reliance on dopaminergic agents due to concerns like augmentation. For our third blog post in this “Crash Course on RLS” series, we will review gabapentinoids as the more recent first-line treatment for RLS. We will talk about the history of gabapentinoids, their mechanisms, and efficacy for RLS symptoms. Understanding non-dopaminergic options is key for patients and providers to develop a comprehensive and personalized treatment plan for better sleep.

History and Mechanism of Gabapentinoids

Gabapentinoids are a class of anti-seizure medications that were originally developed to treat epilepsy or seizures.[1] Gabapentin (brand name Neurontin) was the first in this class to be approved by the Food & Drug Administration (FDA) in 1993, followed by pregabalin (brand name Lyrica) in 2004, and gabapentin enacarbil (brand name Horizant) in 2011.[2,3] Despite the name, gabapentinoids do not directly affect gamma-aminobutyric acid (GABA) receptors. Instead, they work by binding to proteins called alpha-2-delta subunits, which are part of calcium channels in your nerves and brain. Think of these channels as the gates to control the flow of signals in the nervous system. By binding to these receptors, gabapentinoids essentially turn down the release of several excitatory neurotransmitters, or chemical messengers that activate nerve cells.[4] This effect is helpful, especially for controlling seizures and easing pain in areas of the nervous system.

Because of their calming effect on the nervous system, gabapentinoids are now used for more than just epilepsy. They are FDA-approved to treat several specific types of nerve pain, including pain from shingles, diabetic nerve damage, and spinal cord injuries.[4,5] Importantly, gabapentinoids have become the first-line treatment for moderate to severe RLS.[6] They offer an important advantage over older RLS medications called dopamine agonists (such as pramipexole and ropinirole), which can cause a problem called augmentation. Augmentation is characterized by RLS symptoms starting earlier in the day, becoming more severe, and spreading to other body parts like the arms. This problem develops gradually and affects approximately 7% to 10% of patients each year who take dopamine agonists.[7]

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Efficacy of Gabapentinoid Medications for RLS

When it comes to gabapentinoids, particularly gabapentin, gabapentin enacarbil, and pregabalin, studies have found that these medications are both safe and effective. Although all three of these medications are useful for treating RLS, gabapentin enacarbil is FDA-approved for RLS, whereas standard gabapentin is used for off-label RLS treatment.[a] While the risk of augmentation is still present in gabapentinoids, it is much less so than in dopamine agonists. One meta-analysis found that, of 60 studies analyzed with over 11,543 participants, the overall risk of augmentation was 5.6%, with long-term treatment augmentation incidence being 6.1% and short-term treatment being 3.3% for patients using dopamine agonists. However, the risk of augmentation for patients using gabapentinoids was only 0.9%.[x] In 2024, the American Academy of Sleep Medicine released a statement recommending against the use of dopamine agonists while promoting the usage of gabapentinoids as the recommended RLS treatment.[y,z] Gabapentin, gabapentin enacarbil, and pregabalin are primarily recommended due to their moderate-certainty evidence showing clinically meaningful improvements in RLS severity and overall sleep outcomes.[y,z] 

Gabapentin enacarbil is a pro-drug of gabapentin, meaning that the compounds in gabapentin enacarbil are inactive or have low-activity, which are then absorbed by the body and, through chemical or enzymatic metabolism, turn into an active drug.[b] The benefit of this is that gabapentin enacarbil is better absorbed by the body and tends to be more predictable and consistent.[a] In terms of the medication's efficacy, randomized trials have shown that patients who use gabapentin enacarbil have greater improvements in their International Restless Legs Scale (IRLS) scores compared with placebo groups, with one study noting a 13.2 reduction in IRLS score vs a reduction of 8.8 in those who took the placebo.[c] This study also found that 72-77% of patients were clinical responders with the medication compared with about 45% of patients who took the placebo. Both the 600 mg and 1200 mg doses significantly improved RLS symptoms and improved sleep quality, leading to fewer nocturnal awakenings and better daytime functioning.[c] However, the medication is typically prescribed as a single 600 mg dose, with larger doses typically being prescribed for different diseases (such as epilepsy and postherpetic neuralgia).[d,e] Gabapentin enacarbil tends to be well tolerated, with the most common adverse effects being somnolence (excessive drowsiness) and dizziness.[c]

As for pregabalin, the key difference between this medication and standard gabapentin is that pregabalin has a higher absorption rate, is more predictable, and tends to be more potent.[f] Patients who are using pregabalin tend to see an improvement in their IRLS scores and insomnia severity index (ISI) scores.[g] Many studies have also evaluated the effectiveness of pregabalin taken in addition to dopamine agonists when the patient has minimal or no response to the dopaminergic medication. One study evaluated this in 20 patients and found that the addition of pregabalin improved IRLS and ISI scores with no serious adverse effects being observed.[h] This study, along with others, evaluated a dosage of 75 mg, though some studies have evaluated as high as 225 mg.[i] Thus, in patients suffering from RLS with minimal benefits from dopaminergic medications, pregabalin could prove to be a beneficial addition to their current treatment.

Conclusion

Treatment for RLS has shifted over the years, with gabapentinoids like gabapentin enacarbil and pregabalin emerging as the new standard first-line therapy for moderate to severe symptoms. Unlike the previously preferred dopaminergic agents, gabapentinoids affect calcium channels in the nervous system and have a lower risk of causing augmentation. Gabapentinoids offer a safer and highly effective treatment alternative, especially for those who are currently taking dopaminergic medication. However, treatment should always be individualized. Consult with your healthcare provider (or our team at Empower Sleep) to determine the most appropriate medications for your symptoms!