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Treatment for Restless Legs Syndrome (RLS)

Medicine/Drug Therapy

Unfortunately, there is no known cure for restless legs syndrome. At present, there is no one drug which works for everybody, but most individuals with restless legs syndrome will find some benefit and relief with the currently available medications for treating this disorder, which can be divided into several categories: dopamine-related medications, opiates, benzodiazepines receptor agonists (BRAs), alpha-2 delta medications and iron supplementation.

Dopamine-Related Medications

Dopamine is a chemical that is produced by certain cells in the brain and this group of drugs functions to either increase the amount of dopamine made by the cell (levodopa) or increase the dopamine signal to other surrounding cells by mimicking dopamine in the brain. The dopamine-related drugs include levodopa, pramipexole, ropinirole and rotigotine.

These drugs are also used for Parkinson's disease. However, there is no indication that RLS is related to, or is a precursor of, Parkinson's disease. These medications are likely to be effective in reducing symptoms in 90 percent of patients with restless legs syndrome. Excessive sleepiness, increased compulsive behavior and more commonly, augmentation, a paradoxical worsening of symptoms, may occur with these medications after extended use. Learn more about dopamine drugs and possible side effects.


Dr. Willis in his description of this disease in 1685 also reported on the benefits of opiates for treating the symptoms. Thus for over 300 years opiates remained the only truly effective treatment for this disease. This category of medications includes codeine, hydrocodone, oxycodone, morphine, hydromorphone, methadone, buprenorphine and pentazocine.

An estimated 85 percent to 90 percent of patients with RLS will respond very well to opiates. An analysis of drug responses in RLS over a 2 -10 year period showed that 85 percent of RLS patients who started on methadone were still on it compared to less than 20 percent of those started on a dopamine drug. The median starting dose for methadone in this study was 10 mg per day with a range between 2.5 mg and 20 mg per day.

It is important to realize that RLS for a majority of patients is not about pain; it is an abnormal, uncomfortable sensation. Tolerance to the opiates when treating RLS seems to be less of a problem than that seen with treatment of chronic pain disorders.

What is the Role of Opioids in RLS?

Presented by Christopher J.Earley, MB, BCh, PhD of the RLS Foundation Quality Care Center Director at Johns Hopkins Center for Restless Legs Syndrome.

Benzodiazepines Receptor Agonists

This group of drugs is also known as sleeping pills and has valium-like effects. The structure of the parent compound was designated as a benzodiazepine, and later research identified a benzodiazepine receptor. This receptor interacts with a larger GABA receptor. 

Benzodiazepine receptor agonists (BRAs) are newer drugs  that do not have the benzodiazepine structure of the previous parent compound, but still bind to the benzodiazepine receptor. Clonazepam was the treatment of choice for RLS for many years but it is not clear that any one of this class of drugs is better than another for treating RLS. BRAs  such as zolpidem (Ambien®), eszopiclone (Lunesta®), and zaliplon (Sonata®) are shorter acting agents than clonazepam and may be equally effective. BRAs are most effective in those with mild symptoms.

Alpha-2 delta Drugs

These drugs interact with one of the calcium channel proteins, alpha-2 delta protein. Calcium channels allow the charged calcium ion to move into the nerve cell and are therefore important in activating, deactivating and stabilizing the electrical activity of the nerve cell. The alpha-2 delta drugs are also used to treat patients with nerve-damage related pain even in those without RLS. There are currently three drugs that fall into the alpha-2 delta class of drugs: gabapentin (Neurontin®), pregabalin (Lyrica®), and gabapentin enacarbil (Horizant®). 

Gabapentin enacarbil is the only one of these three drugs that has be approved by the FDA (June 2011) for specific use in RLS, although the other two drugs have been used in treatment trial of RLS. Gabapentin enacarbil is a prodrug to gabapentin, which means the compound is converted into gabapentin and thus acts like gabapentin in the brain. Its advantage over regular gabapentin is that it is more consistently absorbed and is much longer lasting. A clinical trial of the effects of pregabalin versus pramipexole in RLS patients over 1 year showed pregabalin to be significantly better than pramipexole in improving the severity of RLS symptoms. The alpha-2 delta drugs are an effective treatment option for many patients with RLS and should be considered one of the choices for first line treatment of RLS.

Iron Supplementation

The significance of low iron in causing RLS is outlined in the segment on Causes of Restless Legs Syndrome

Since the 1950s, it has been known that iron therapy, even without the presence of anemia has benefits for RLS symptoms. Studies have shown a strong relation between body iron stores as determined by serum ferritin and the severity of the RLS symptoms. A study has shown that in patients whose serum ferritin was < 75 µg/l, oral iron therapy (325 mg ferrous sulfate twice a day on an empty stomach) on average improved RLS symptom after 3 months.  

A recent study has shown that giving oral iron more than once a day or at a dose greater than 85 mg per day does not necessary lead to a greater increase in absorbable iron. Oral iron equivalent to 65-85 mg of elemental iron will be best absorbed if given once a day.  It should NOT be given with solid or liquid food/dietary supplements or with milk.  It should be given on an empty stomach an hour before eating or two hours after eating along with 100-200 mg of vitamin C. An iron panel (early morning fasting blood to check iron, ferritin, TIBC, and percent iron saturation) should be done after three months to check on progress of the treatment. Oral iron should be stopped 2 days before the iron studies are done.  The goal is to get the serum ferritin above 100 µg/l.

If the patient cannot tolerate the iron, or, if after three months there has been very little change in the iron stores, an iron infusion may be appropriate. Delivering iron directly into the blood by vein allows the iron to bypass the gastrointestinal tract, which can limit absorption of iron when iron is given orally. Several different formulations of iron are designed for intravenous treatment and are used for the treatment of anemia. Two formulations of iron dextran exist (Dexferrum and INFeD), with the low molecular weight (LMW) iron dextran (INFeD) demonstrating better safety profile than the older version of iron dextran, Dexferrum (Chertow et al. Nephrol Dial Transplant 2004:19,1571). Other iron formulations currently available for intravenous use include: iron sucrose (Venofer®), iron gluconate (Ferrlicit®), ferumoxytol (Feraheme®) and ferric carboxymaltose (Ferinject®).

Two, randomized, double-blind, placebo-controlled clinical studies using 1000 mg of ferric carboxymaltose versus placebo (subjects just received the solution with no iron in it), have shown that RLS patients who received the iron had significantly greater improvement in RLS symptoms (Allen et al. Sleep Medicine 2011: 12, 906; Cho et al. Sleep Medicine 2016:25,16). None of these patients had an anemia and some of the subjects has serum ferritin values of greater than 100 ug/l before the iron infusion. Approximately 35 percent of subjects who had received the iron treatment still remained off of all RLS medications even 6 months after the treatment. 

From clinical experience in using LMW iron dextran (INFeD) in RLS patients, we find that the maximum effect of the iron infusion may take as long as six weeks. As part of our clinical practice, we will repeat an early-morning, fasting iron panel about 8 weeks after the infusion to establish the new iron status and may repeat another iron panel in about two months to make sure that the iron levels are stable and not dropping.  

Non-Drug Treatments

Several non-drug related treatments that most patients suffering with this disorder already appreciate include hot baths, massaging and rubbing the legs, applying hot or cold packs, restricting the amount of caffeine or alcohol and partaking in moderate physical exercise. Any of  these methods may bring about some level of relief from the symptoms, but in the end, many of these patients will still be unable to have a good night of sleep.

To make an appointment or request an evaluation, please call the Johns Hopkins Sleep Disorders Center at 410-550-5864.

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Maryland Patients

To make an appointment with one of our Restless Legs Syndrome physician specialists, please call 410-550-5864.
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Adult Neurology: 410-955-9441
Pediatric Neurology: 410-955-4259
Adult Neurosurgery: 410-955-6406
Pediatric Neurosurgery: 410-955-7337


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