Iron Over Dopamine? Restless Legs Syndrome Guidelines Revamp

To reduce the risk for complications, the use of dopaminergic agonists in the treatment of severe restless legs syndrome (RLS) has become less common.
RLS is characterized by an irresistible urge to move the legs, often accompanied by unpleasant sensations such as itching, tingling, or electric paresthesia, which typically affect the lower limbs. It affects 8% of the French population, predominantly women.
New guidelines from the American Academy of Sleep Medicine (AASM) no longer recommend the use of these drugs as first-line treatments.
During the recent French Language Neurology Days in Montpellier, France, Sofiène Chenini, PhD, a researcher at the Sleep-Wake Disorders Unit, Department of Neurology, Gui-de-Chauliac Hospital, reviewed the current treatment approaches for RLS and highlighted non-dopaminergic alternatives. He cautioned that dopaminergic agonists could lead to the augmentation and worsening of symptoms over time.
In France, RLS is guided by the 2019 recommendations of the French Society for Sleep Research and Medicine (SFRMS), which still supports the use of dopaminergic agonists for the most severe cases of RLS.
'For now, we have not updated the guidelines, but we are considering it,' said Chenini, referring to the new American recommendations.
Iron as First Line
According to the new AASM guidelines, intravenous iron supplementation is the preferred first-line treatment for severe RLS. In some cases, second-line antiepileptic drugs are considered a first-line treatment option in French recommendations when the severity is low.
These sensations of restlessness typically occur in the evening or at night during periods of rest or inactivity and are temporarily relieved by movement, such as walking and stretching. The condition often leads to repeated leg movements during sleep and difficulty falling asleep due to increased brain activity.
RLS is not fully understood but is often linked to problems with iron regulation.
MRI studies have shown iron deficiency in the brains of patients with RLS. This suggests a disruption in iron transport across the blood-brain barrier and into neurons, possibly due to a decrease in the transferrin receptor.
This disruption in iron regulation, believed to have a primarily genetic origin, induces an increase in the synthesis of dopamine and glutamate, which is likely the cause of the symptoms. In RLS, changes in the dopaminergic system are linked to risk factors such as aging and the use of certain medications.
Five Clinical Criteria
According to a 2016 consensus from the SFRMS, RLS diagnosis is based on five clinical criteria:
An intense and irresistible urge to move the lower limbs accompanied by unpleasant sensations Worsening symptoms at rest, the patient is unable to stay still Relief of symptoms through movement such as walking or stretching Increased severity of symptoms in the evening and at night The absence of other causes, such as myalgia, fibromyalgia, osteoarthritis, venous insufficiency, and obliterative arteriopathy of the lower limbs
Once diagnosed, iron assessment is required to check for iron deficiency. The analysis includes measuring C-reactive protein to ensure there is no inflammation, 'which reduces iron bioavailability,' Chenini explained.
Therefore, polysomnography remains optional in such cases. If ferritin levels are below 75 µg/L, iron supplementation is recommended. Treatment also involves addressing factors that worsen symptoms, such as caffeine and alcohol consumption and smoking. It is advisable to stop or switch medications that may aggravate symptoms, such as antidepressants and antihistamines.
The antidepressants involved are serotonergic, particularly serotonin reuptake inhibitors, with a long half-life.
'If stopping treatment is not possible, switching to antidepressants with a short half-life, such as venlafaxine or duloxetine taken in the morning, is recommended,' he said.
Lifestyle
For mild RLS cases, lifestyle changes may be sufficient to ease symptoms. These include avoiding coffee, alcohol, and tobacco; maintaining regular sleep and wake times; engaging in physical activity early in the day; and performing stretching exercises before sleeping.
If ferritin levels remain low after 3 months of iron supplementation, switching to intravenous treatment is recommended. Options included a single dose of ferric carboxymaltose (500-1000 mg) or multiple sessions of 200 mg ferric hydroxide-sucrose.
If symptoms persist, a mild opioid is recommended as needed, starting with opium powder, codeine (such as paracetamol-codeine 500/30 mg, up to 60 mg of codeine or more), and tramadol (starting at 50 mg and increasing to 100 mg if necessary).
If the improvement remains insufficient, specific treatment should be considered on the basis of the severity of RLS assessed using the International Restless Legs Syndrome Severity Scale (IRLS) score. Background treatment is recommended for very severe cases (IRLS score above 30), which are linked to the risks for depression and even suicide, as noted by Chenini. It is also advised in cases of severe insomnia or when the quality of life is significantly affected.
A recent study by Chenini and colleagues found a 10-fold higher risk for depressive symptoms in patients with RLS, particularly in young women with insomnia. The study also reported a threefold increase in suicidal thoughts.
Dose and Misuse
According to the French guidelines, very severe cases of RLS require treatment with low-dose dopamine agonists, such as pramipexole, rotigotine, or ropinirole. These drugs may also help reduce motor inhibition in patients with depression. Dopamine agonists are the only approved treatment for this indication.
'It is essential to respect the maximum dosages,' Chenini emphasized. The recommended maximum doses are 3 mg for rotigotine, 0.54 mg for pramipexole, and 4 mg for ropinirole.
Second-line treatments include alpha-2 delta ligand antiepileptics, such as gabapentin and pregabalin, especially in cases of severe insomnia. For less severe cases, these antiepileptics are preferred as first-line treatment. Gabapentin may be favored over pregabalin because it causes less sedation.
The major risk associated with dopamine agonists is worsening symptoms after prolonged use, known as augmentation syndrome, which is particularly higher in patients with iron deficiency, older age, and those prescribed high doses of antagonists.
Concerns about this complication led the AASM to remove dopamine agonists from the recommendations for RLS management.
In 2016, American guidelines similar to the current French recommendations for dopamine agonists were the first-line treatment alongside antiepileptics in the treatment of severe forms of the disease. The new recommendations now place intravenous iron supplementation as the first-line treatment, while antiepileptics are the second line.
Chenini highlighted that this change is due to the misuse of dopamine agonists in RLS. A registry of 670,000 patients with RLS in the United States showed that 60% were treated with dopamine agonists, and 20% received doses exceeding the recommended limits.
The registry shows that neurologists prescribe higher doses of dopamine agonists for RLS than general practitioners. This is likely because these drugs are also used to treat Parkinson's disease, where the doses are approximately 10 times higher than those used for RLS.
Chenini reported having no conflicts of interest.

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