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Restless legs syndrome and related disorders

Description

An in-depth report on the causes, diagnosis, treatment, and prevention of RLS.

Alternative Names

Ekbom's syndrome; Nocturnal leg cramps; Periodic limb movement disorder

Medications

The American Academy of Sleep Medicine recommends medications for RLS or periodic limb movement disorder (PLMD) only for persons who fulfill strict diagnostic criteria, and who experience excessive sleepiness that occurs as a result of these conditions. Little is known about the best way to treat RLS, but some experts suggest the following:

• Over-the-counter pain relievers and possibly mineral and vitamin supplements (particularly folic acid in people who might be deficient) should be tried first.
• People with RLS should be tested for iron deficiency and, if they are, treated with oral iron supplements.
• Dopaminergic drugs (drugs that increase levels of dopamine) are the standard drugs for treating severe RLS, PMLD, or both. These drugs include dopamine precursors such as levodopa (L-dopa) as well as dopamine receptor agonists such as pergolide, pramiprexole, and ropinirole. Some experts then recommend regular use of dopamine receptor agonists for patients who experience nightly symptoms and fast-acting L-dopa combinations for those whose symptoms occur only occasionally.
• If dopaminergic drugs fail or for patients who have frequent -- but not nightly -- symptoms, other drugs may be helpful. These include opiates (pain relievers), benzodiazepines (sedative hypnotic drugs), or anticonvulsants. However, benzodiazepines and opiates can become habit forming and addictive.

Tylenol and Non-Steroidal Anti-Inflammatories (NSAIDs)

Before taking stronger medications, people should try over-the-counter pain relievers, such as acetaminophen (Tylenol) or nonsteroidal anti-inflammatory drugs (NSAIDs), which include ibuprofen (Advil, Motrin, Rufen), naproxen (Anaprox, Naprosyn, Aleve), and ketoprofen (Orudis KT, Aktron).

Although NSAIDs work well, long-term use can cause stomach problems, such as ulcers and bleeding, and possible heart problems. In April 2005, the FDA asked drug manufacturers of NSAIDs to include a warning label on their product that alerts users of an increased risk for cardiovascular events and gastrointestinal bleeding.

Levodopa and Other Dopaminergic Drugs

Dopaminergic drugs increase the availability of the brain chemical dopamine and are the first-line treatment for severe RLS and PLMD. These drugs significantly reduce the number of limb movements per hour and improve the subjective quality of sleep. Patients with either condition who take these drugs have experienced up to 100% reduction in symptoms. However, these drugs, which are ordinarily used for Parkinson's disease, can have severe side effects. They do not appear to be as helpful for RLS related to hemodialysis as RLS from other causes. Dopaminergic drugs include dopamine receptor agonists and dopamine precursors.

Dopamine Receptor Agonists. Dopamine receptor agonists (also called dopamine agonists) are increasingly being used as alternatives to L-dopa. Because they have fewer side effects than L-dopa, including rebound effect, and augmentation, these drugs may be used on a daily basis. They have been shown to relieve symptoms in up to 70 - 90% of patients. Dopamine agonists can be categorized as ergot-derived (such as pergolide, cabergoline) or non-ergot derived (such as pramipexole, ropinirole). The newer non-ergotamine derivatives may induce fewer side effects than ergot-derived drugs. Studies on these medications report the following:

• Ropinirole (Requip) is a non-ergotamine dopamine agonist. Approved in 2005, ropinirole is the first and only drug approved specifically for treatment of moderate-to-severe RLS (more than 15 RLS episodes a month). Side effects are generally mild but may include nausea, vomiting, drowsiness, and dizziness.
• Pergolide (Procalamine) is as effective as carbidopa-levodopa and has fewer side effects, though nausea, dizziness, and nasal stuffiness are common. It also seems to produce fewer of the rebound and augmentation effects of levodopa, particularly at higher doses. Benefits persist for at least a year.
• Pramipexole (Mirapex) is showing good results in clinical trials for improving symptoms and quality of life in patients with RLS. A long-term, follow-up study showed the drug continued to be effective for RLS, even after 7 months of use. However, some research suggests that RLS symptoms may rapidly worsen when the drug is discontinued. The most common side effects of pramipexole include nausea, headache, and tiredness.
• Cabergoline (Dostinex) is also showing promise in clinical trials. In one study, cabergoline was used for RLS after levodopa had either failed or resulted in increased symptoms. Patients in the study reported relief or freedom from symptoms after 4 weeks of use. A 2006 study indicated that a single evening dose of cabergoline improved both day and nighttime limb movements, and sleep disturbances.

Other Dopamine Agonists. Rotigotine is a unique dopamine agonist that is being developed in patch form for RLS and Parkinson's disease. Other dopamine agonists that have shown some promise in small studies include alpha-dihydroergocryptine, or DHEC (Almirid), and piribedil (Trivastal).

Dopamine Precursors. The dopamine precursor levodopa (L-dopa) is often used for severe RLS. The standard preparations (Sinemet, Atamet) combine levodopa with carbidopa, which improves the action of levodopa and reduces some of its side effects, particularly nausea. Levodopa can also be combined with benserazide (Madopar) with similar results, but Sinemet is almost always used in America. (Levodopa combinations are shown to be well tolerated and safe.)

Patients typically start with a very low dose taken 1 hour before bedtime. The dosage is increased until the patient finds relief. Patients sometimes need to take an extended form or to take it again during the night.

Levodopa has a rapid onset of action, and effectiveness is usually achieved within the first few days of therapy. One study reported that a combination therapy of regular-release L-dopa plus sustained release L-dopa was effective in improving sleep.

Serious common side effects of L-dopa treatment are augmentation and rebound. (See side effects section for more information.) Many studies report that augmentation (worsening of symptoms earlier in the day) occurs in up to 70% of patients who take L-dopa. The risk is highest for patients who take daily doses, especially doses at high levels (greater than 200 mg). For this reason, experts recommend that L-dopa should only be used intermittently (fewer than three times per week) and that the drug should be immediately discontinued if augmentation does occur. Following withdrawal from L-dopa, patients can switch to a dopamine receptor agonist.

Regimens. L-dopa is fast acting and takes only 15 - 30 minutes before it is effective. The dopamine receptor agonists take at least 2 hours to start working. Some experts recommend regular use of dopamine receptor agonists for patients who experience nightly symptoms and L-dopa for those whose symptoms occur only occasionally.

Side Effects. Common side effects of all these drugs vary but may include feeling faint or dizzy (especially when standing up), headaches, abnormal muscle movements, rapid heartbeat, insomnia, bloating, chest pain, and dry mouth. Nausea may be especially common. Adding the drug domperidone may help to relieve this side effect. Because these drugs may also cause daytime drowsiness, special care should be taken when driving. In rare cases, they can cause hallucinations or lung disease.

Dopaminergic drugs may also have the following side effects, which can be limiting factors in the value of these medications for RLS. (They tend to be more severe with L-dopa than the newer dopamine receptor agonists.)

• Rebound Effect. The rebound effect causes increased leg movements at night or in the morning as the dose wears off.
• Augmentation. Long-term use of these drugs may eventually intensify symptoms of restless legs syndrome in the late afternoon or evening. Symptoms of restlessness, in severe cases, extend to the upper part or the whole body and may occur when walking. About 30% of patients who take the dopamine receptor agonists have reported augmentations symptoms compared to 70% who take L-dopa. As the newer drugs are taken for longer periods and at higher doses, however, their augmentation rates may become closer to those of L-dopa. In general, however, occasional use of any drug poses a very a low risk for augmentation.
• Tolerance (Loss of effectiveness). Long-term use can lead to loss of effectiveness. Adding a drug called entacapone (Comtan) may prolong the duration of action of carbidopa-levodopa therapy (Sinemet), but it can cause nausea.

Using the lowest dose possible can minimize these effects.

Withdrawal Symptoms. Patients who withdraw from these drugs typically experience very severe RLS symptoms for the first two days after stopping. RLS eventually returns to pre-treatment levels after about a week. The longer the drugs have been taken, the worse the withdrawal symptoms.

Benzodiazepines

Benzodiazepines, such as clonazepam (Klonopin), are commonly called sedative hypnotics and are used for insomnia and anxiety. They may be helpful for some patients with RLS that disrupts sleep. Clonazepam may be particularly helpful for children with both periodic limb movement disorder and symptoms of attention-deficit hyperactivity disorder. It also appears to be helpful for patients with RLS who are undergoing hemodialysis.

Side Effects. Elderly people are more susceptible to side effects and should usually start at half the dose prescribed for younger people and should not take long-acting forms. Side effects may differ depending on whether the benzodiazepine is long- or short-acting.

• The drugs may increase depression, a common co-condition in any case in many people with insomnia.
• Breathing problems may occur with overuse or with people with pre-existing respiratory illness.
• Long-acting drugs have a very high rate of residual daytime drowsiness compared to others. They have been associated with a significantly increased risk for automobile accidents and falls in the elderly particularly in the first week after taking them. Shorter-acting benzodiazepines do not appear to pose as high a risk.
• Memory loss (so-called traveler's amnesia), sleepwalking, and odd mood states have been reported after taking triazolam (Halcion) and other short-acting benzodiazepines. These effects are rare and probably enhanced by alcohol.
• Because these drugs cross the placenta and enter breast milk, pregnant nursing women should not use them. An association was reported between the use of benzodiazepines in the first trimester of pregnancy and the development of cleft lip in newborns.
• In rare cases, overdoses have been fatal.

Interactions. Benzodiazepines are potentially dangerous when used in combination with alcohol. Some drugs such as the ulcer medication cimetidine can slow the breakdown of the benzodiazepine.

Withdrawal Symptoms. Withdrawal symptoms usually occur after prolonged use and indicate dependence. They can last 1 - 3 weeks after stopping the drug and may include:

• Gastrointestinal distress
• Sweating
• Disturbed heart rhythm
• In severe cases, patients might hallucinate or experience seizures, even a week or more after the drug has been stopped.

Rebound Insomnia. Rebound insomnia, which often occurs after withdrawal, typically includes one to two nights of sleep disturbance, daytime sleepiness, and anxiety. The chances for rebound are higher with the short-acting benzodiazepines than with the longer-acting ones.

Narcotic Pain Relievers

Narcotics are pain-relieving drugs that act on the central nervous system. They are sometimes prescribed for severe cases of RLS. They may be a good choice if pain is a prominent feature. Some evidence also suggests that narcotics reduce the frequency of periodic leg movements.

There are two types of narcotics, both of which have been used in RLS:

• Opiates are derived from natural opium (morphine and codeine). Some patients report relief with the use of the opiate fentanyl (Duragesic), used in skin patch form. An implanted abdominal pump (Isomed) uses morphine and an anesthetic called bupivacaine. Investigate work is showing promise for patients with severe RLS.
• Opioids are synthetic drugs. The most common example is oxycodone (Percodan, Percocet, Roxicodone, Oxycontin). Apomorphine is a morphine derivative. In one study, when it was injected under the skin at night, it reduced nocturnal discomfort and leg movements in some patients.

Although the use of narcotics for severe RLS is controversial, some studies have suggested that they are rarely addictive for pain sufferers except among patients with a history of substance abuse, even when they are prescribed long-term. The use of such drugs may be beneficial when included as part of a comprehensive pain management program. Such a program involves screening prospective patients for possible drug abuse and then regularly monitoring those who are taking it, adjusting the dose as necessary to achieve an acceptable balance between pain relief and side effects. Patients on long-term opiate therapy should also be monitored periodically for sleep apnea, a condition that causes breathing to stop for short periods many times during the night and which may exacerbate symptoms of RLS, insomnia, and other complaints.

Tramadol. Tramadol (Ultram) is a pain reliever that has been used as an alternative to opioids. In one study, tramadol was very effective for RLS and produced few or no side effects. It has opioid-like properties, but is not as addictive. (Dependence and abuse have been reported, however.) Nevertheless, withdrawal after long-term use (longer than a year) can cause intense symptoms, including diarrhea, insomnia, and even restless legs syndrome itself.

Antiseizure Drugs

Antiseizure drugs, such as gabapentin (Neurontin), valproic acid (valproate, divalproex, Depakote, Depakene), and carbamazepine (Tegretol), relax blood vessels and are being tested for RLS. Gabapentin, a newer antiseizure drug, is showing particular promise for mild to moderate RLS. A 2002 study reported that it improved RLS symptoms and sleep, particularly in patients who also experienced pain. It was also effective for periodic leg movement disorder.

Side Effects. All antiseizure drugs have potentially severe side effects and should be tried only after non-drug methods have failed. Side effects of many anti-seizure drugs include nausea, vomiting, heartburn, increased appetite with weight gain, hand tremors, irritability, and temporary hair thinning and loss (taking zinc and selenium supplements may help reduce this effect). Some can also cause birth defects and, in rare cases, liver toxicity. Gabapentin may have fewer of these side effects than valproic acid or carbamazepine.

Other Drugs

Selective Serotonin Reuptake Inhibitors (SSRIs) and Similar Antidepressants. Imbalances in the neurotransmitter serotonin have been associated with RLS. To correct these imbalances, some patients can try the common antidepressants known as SSRIs, which increase serotonin levels in the brain. One study found that SSRIs reduced RLS in 58% of patients and eliminated symptoms in 12%. SSRIs include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), and citalopram (Celexa, Cipramil).

Bupropion (Wellbutrin), a newer so-called designer antidepressant that has slightly different actions, may also be helpful for RLS. These drugs are not addictive and do not have the severe side effects of other RLS drugs, but more research is warranted to determine if they are useful.

Clonidine. Clonidine (Catapres), a drug used for high blood pressure, is helpful for some patients and may be an appropriate choice for patients who have RLS accompanied by hypertension. It also may help patients with RLS who are undergoing hemodialysis.

Baclofen. The anti-spasm drug baclofen (Lioresal) appears to reduce intensity of RLS (although not frequency of movements).

• Review Date: 10/18/2006
• Reviewed By: Harvey Simon, M.D., Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

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