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Treatment for Restless Legs Syndrome (RLS)

Medicine/Drug Therapy

Unfortunately, there is no known cure for restless legs syndrome. At the present time, 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.

The medications presently available for treating this disorder can be divided into several categories:

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% of patients with restless legs syndrome. Excessive sleepiness, increased compulsive behavior and more commonly, paradoxical worsening of symptoms, referred to as “augmentation”, 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 1685s 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. It is estimated that 85-90% 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% of RLS patients who started on methadone were still on it compared to less than 20% 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.

Benzodiazepines Receptor Agonist (BRA)

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”.  Later research identified the specific target of the benzodiazepine drugs and designated it as the “benzodiazepine receptor”.  This receptor interacts with a larger receptor called the GABA receptor.  More recently, new drugs have been developed, which do not have the benzodiazepine structure of the previous parent compound but still bind to the benzodiazepine receptor, so the new classification of these drugs is “Benzodiazepine Receptor Agonist”.   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.  The newer BRAs including Zolpidem (Ambien), Eszopiclone (Lunesta), and Zaliplon (Sonata) are shorter acting agents than clonazepam and may be equally effective.  The BRAs are most effective in those with mild symptoms.

Alpha-2 delta Drugs

These drugs have their affect by interacting 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, in deactivating and in 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 after you take the pill it 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 recent 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 1950, 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 sulphate twice a day on an empty stomach) on average improved RLS symptom after 3 months.  A randomized, double-blind study of the effects of giving a 1000 mg of iron in a pint of fluid through a vein in the arm (intravenously) versus no iron, found that nearly 50% of patients had moderate or greater improvement in their symptoms. A little over 20% of those in the study had a near complete resolution of their RLS symptoms with the iron infusion. All of the patients in this study had normal hemoglobins (i.e., not anemic) and had a range of serum ferritin that were mostly in the normal range.

Oral iron equivalent to 65 mg elemental iron may be given once, twice or three times 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 every three months to check on progress of the treatment.  The goal is to get the serum ferritin above 100 µg/l.  If the patient cannot tolerate the iron or if after 6 months there has been very little change in the iron stores than consider an iron infusion.

By delivering iron directly into your blood via the vein, an iron infusion bypasses the gastrointestinal tract, which acts to limit absorption of iron when iron is given orally.  There are several different formulations of iron which are designed for intravenous treatment and are used for the treatment of anemia.  There are two formulation of iron dextran, with the newer, low molecular weight (LMW) iron dextran (INFeD) appearing to be much safer than the older version of iron dextran, Dexferrum (Chertow et al.  Nephrol Dial Transplant 2004:19, 1571).  The other iron formulations that are currently approved for treating anemia include: iron sucrose (Venofer), iron gluconate (Ferrlicit), ferumoxytol (Feraheme) and ferric carboxymaltose (Ferinject). In a randomized, double-blind trial of 1000 mg of ferric carboxymaltose versus placebo (subjects just received the solution with no iron in it), the RLS patients who received the iron had significantly greater improvement in RLS symptoms (Allen et al.  Sleep Medicine 2011: 12, 906). None of these patients had an anemia and their serum ferritin ranged from 5- 113 ug/l prior to the iron infusion.  Twenty weeks after a total 1000 mg of iron had been infused about 35% of patients had still remained off of all RLS medications. 

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 much as 4-6 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. We may repeat another iron panel in about 2 months to make sure that the iron levels are stable and not dropping.  

Non-Drug Related Treatment Options

There are some non-drug related treatments that most patients suffering with this disorder already appreciate. 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 will all bring about some level of relief from the symptoms. But in the end, many of these will not permit the patient to have a good night of sleep.

To make an appointment or request an evaluation, please call the Johns Hopkins Sleep Disorders Center at 410-550-0571.


Our Experts in the News

Restless Legs Syndrome, Insomnia And Brain Chemistry: A Tangled Mystery Solved?

Dr. Christopher Earley speaks on:

"Iron status and iron treatment."

"What is augmentation and how should it be treated?"

"What is the evidence for the iron-dopamine hypothesis?"

Related Articles

"Restless Legs Syndrome"
New England Journal of Medicine
Willis-Ekbom Disease (aka Restless Legs Syndrome) Foundation’s Educational Pamphlets and Brochures

Volunteers Needed

If you are interested in participating in a clinical study being conducted at the Johns Hopkins Center for RLS, please contact the RLS Center Study Recruiter at 410-550-1046.

Out-of-State and International Patients - Find Out More


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