In a major shift, sleep medicine experts now recommend iron supplements and gabapentin-type drugs as first-line treatments for restless legs syndrome, moving away from dopamine agonists that can make symptoms worse over time.
The 2025 guidelines from the American Academy of Sleep Medicine mark what experts call a paradigm shift in managing the condition, which affects an estimated 5% to 10% of adults in the United States.
Why the Change?
For years, dopamine agonist medications such as pramipexole and ropinirole were standard treatments for restless legs syndrome. The new guidelines stop recommending their long-term use due to a troubling phenomenon called augmentation.
"The brain eventually gets used to dopamine agonists, diminishing their effectiveness over time and requiring higher doses for symptom relief," said Dr. John Winkelman, a Harvard Medical School professor who contributed to the guidelines.
Even more concerning, augmentation can cause symptoms to become more severe, spread from the legs to the arms and occur during daytime hours rather than just at night.
People get into real trouble when they take dopamine agonists long-term and start to need higher doses to ease their worsening symptoms.
Elevated doses can cause additional problems including confusion, depression and impulse control disorders such as compulsive gambling or shopping.
Iron Takes Center Stage
One of the most significant changes in the new guidelines is the elevation of iron evaluation and supplementation as a cornerstone of treatment.
Research suggests that low brain iron is an important underlying cause of restless legs syndrome, even in patients whose blood tests show normal iron levels. The guidelines now recommend checking iron levels in everyone with the condition.
For adults with restless legs syndrome, the guideline provides a strong recommendation for intravenous ferric carboxymaltose and conditional recommendations for two other formulations of intravenous iron and oral ferrous sulfate.
"The new recommendations reflect evidence suggesting that low brain iron is an important underlying cause of restless legs syndrome," the AASM noted in announcing the guidelines.
Gabapentinoids Now First-Line
The guidelines give strong recommendations for medications known as alpha-2-delta ligand calcium channel blockers: gabapentin enacarbil, gabapentin and pregabalin.
Unlike dopamine agonists, these drugs work by quieting the central nervous system and do not cause augmentation. They may be particularly useful for patients who also experience pain or anxiety along with their restless legs symptoms.
Gabapentin enacarbil, sold under the brand name Horizant, is specifically approved by the FDA for restless legs syndrome, while regular gabapentin and pregabalin are used off-label.
A Wearable Device Option
For patients seeking non-drug alternatives, the guidelines offer a conditional recommendation for bilateral high-frequency peroneal nerve stimulation.
The FDA has approved the NTX100 Tonic Motor Activation System, a wearable device that stimulates the peroneal nerves in the legs before bedtime. Clinical trial data showed the device significantly reduces symptoms in patients with moderate-to-severe restless legs syndrome.
The device is worn on both legs for about 30 minutes before sleep and works by activating specific nerve pathways that appear to calm the urge to move.
What Patients Should Know
For patients currently taking dopamine agonists, experts caution against stopping medication abruptly. The transition to alternative treatments should be done gradually under medical supervision, as sudden discontinuation can cause severe symptom flares.
The guidelines suggest patients and doctors consider:
- Getting iron levels tested, including ferritin levels, even if previous blood work appeared normal
- Discussing a gradual transition from dopamine agonists if currently using them
- Trying gabapentin or pregabalin as alternatives
- Considering the TX100 device for those who prefer non-drug options
- Addressing lifestyle factors such as caffeine and alcohol use, which can worsen symptoms
Looking Ahead
Research into restless legs syndrome continues to advance. A 2025 study published in Neurological Research explored serum neurofilament light chain as a potential biomarker for the condition, which could eventually help doctors better diagnose and monitor patients.
Scientists are also working to better understand the genetics of restless legs syndrome, which tends to run in families. Improved understanding of the underlying mechanisms could lead to more targeted treatments in the future.
For the millions of Americans who experience the irresistible urge to move their legs at night, these new guidelines offer hope for more effective, sustainable treatment options.
