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Restless Legs Syndrome and Other Sleep-Related Leg 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; Restless Legs Syndrome

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 agents (drugs that increase levels of dopamine) are the standard agents to date 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 RLS patients who experience nightly symptoms and fast-acting L-dopa combinations for those whose symptoms occur only occasionally.
  • If dopaminergic agents fail or for patients who have frequent--but not nightly--symptoms, other agents may be helpful. These include opiates (pain relievers), benzodiazepines (sedative hypnotic drugs), or anticonvulsants.

Over-the Counter Drugs and Supplements

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).

Over-the Counter Supplements. The following supplements may have some benefit:

  • Some people report that vitamin E (800 to 1200 IU per day) may help.
  • Calcium, magnesium, or potassium supplements have helped some people.
  • People who have folate deficiencies should take supplements of folic acid. This is particularly important during pregnancy, when folate deficiencies have been associated with RLS. (And, more importantly, deficiencies also increase the risk for birth defects in the infant.)
Vitamin B9 benefits
Folate (folic acid) is necessary for the production of red blood cells and for the synthesis of DNA (which controls heredity and is used to guide the cell in its daily activities). Folic acid also helps with tissue growth and cell function. In addition, it helps to increase appetite when needed and stimulates the formation of digestive acids.

Iron Supplements

In people with RLS who are also iron deficient, iron supplements can produce a significant reduction in symptoms. They should be used in these patients, however, only when dietary measures have failed. They do not appear to be useful for RLS patients with normal or above normal iron levels. One interesting study, however, reported that high-dose intravenous iron therapy improved symptoms in nearly all patients with normal iron levels, suggesting that iron therapy may be useful in general for RLS. It should be noted, however, that iron replacement therapy can cause gastrointestinal problems, sometimes severe ones. Excess iron may also contribute to heart disease, diabetes, and certain cancers.

Supplement Forms. To replace iron, the preferred forms of iron tablets are ferrous salts, usually ferrous sulfate (Feosol, Fer-In-Sol, Mol-Iron). Other forms include ferrous fumarate (Femiron, FerroSequels, Feostat, Fumerin, Hemocyte, Ircon), ferrous gluconate (Fergon, Ferralet, Simron), polysaccharide-iron complex (Niferex, Nu-Iron), and carbonyl iron (Elemental Iron, Feosol Caplet, Ferra-Cap). Specific brands and forms may have certain advantages. The following are some examples:

  • Prolonged-release ferrous sulfate (Slow Fe) may enhance iron absorption with fewer side effects than standard ferrous sulfate pills.
  • FerroSequels contains a stool softener, which helps prevent constipation.
  • Polysaccharide-iron complex has fewer side effects and equal absorption rates compared to ferrous salts. It is very expensive, however.
  • Carbonyl iron is composed of very fine tiny uniform spheres of iron powder and may prove to be less toxic than ferrous iron.
  • Coated or combination pills do not appear to offer any additional advantages and may hinder absorption of the iron.

Regimen. A reasonable approach for patients with RLS is to take 65 mg of iron (or 325 mg of ferrous sulfate) along with 100 mg of vitamin C on an empty stomach three times a day.

IMPORTANT: As few as three adult iron tablets can poison children, even fatally. This includes any form of iron pill. No one, even adults, should take a double dose of iron if one is missed.

Tips for taking iron are as follows:

  • For best absorption, iron should be taken between meals. (Iron may cause stomach and intestinal disturbances, however, and some experts believe that low doses of ferrous sulfate can be taken with food and absorbed without side effects.)
  • One should always drink a full eight ounces of fluid with an iron pill.
  • Tablets should be kept in a cool place. (Bathroom medicine cabinets may be too warm and humid, which may cause the pills to disintegrate.)
  • One study suggested that iron supplements impeded the absorption of non-heme iron (found in legumes and other vegetables) but not heme iron (contained in meat).

Side Effects. Common side effects of iron supplements include the following:

  • Constipation and diarrhea are very common. They are rarely severe, although iron tablets can aggravate existing gastrointestinal problems such as ulcers and ulcerative colitis.
  • Nausea and vomiting may occur with high doses, but can be controlled by taking smaller amounts. Switching to ferrous gluconate may help some people with severe gastrointestinal problems.
  • Black stools are normal when taking iron tablets. In fact, if they do not turn black, the tablets may not be working effectively. This tends to be a more common problem with coated or long-acting iron tablets.
  • If the stools are tarry looking as well as black, if they have red streaks, or if cramps, sharp pains, or soreness in the stomach occur, gastrointestinal bleeding may be causing the iron deficiency and the patient should call the physician promptly.
  • Acute iron poisoning is rare in adults, but can be fatal in children who take adult-strength tablets.

Interactions With Other Drugs. Certain medications, including antacids, can reduce iron absorption. Iron tablets may also reduce the effectiveness of other drugs, including the antibiotics tetracycline, penicillamine, and ciprofloxacin and the anti-Parkinson's Disease drugs methyldopa, levodopa, and carbidopa. At least two hours should elapse between doses of these drugs and iron supplements.

Supplementary Agents. The following agents may improve iron absorption:

  • Adding either ascorbic acid (vitamin C) or succinic acid to ferrous sulfate therapy will improve absorption of iron stores. Ascorbic acid added to iron therapy, however, may exacerbate some of the side effects. Succinic acid added to ferrous sulfate does not appear to increase side effects.
  • Some studies have found that the addition of zinc to iron supplements increases hemoglobin levels more than iron alone. (Some evidence for this suggests that zinc affects a hormone called insulin-like growth factor-I (IGF-I), which plays a role in the regulation of red blood cell production.)

Levodopa and Other Dopaminergic Agents

Dopaminergic agents 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 have experienced up to 100% reduction in symptoms.However, these drugs, which are ordinarily used for Parkinsons 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 agents include dopamine precursors and dopamine receptor agonists.

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 one 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.

Dopamine Receptor Agonists. Agents known as 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 to 90 percent of patients. Dopamine agonists can be categorized as ergot-derived (e.g., pergolide, cabergoline) or non-ergot derived (e.g., pramipexole, ropinirole). The newer non-ergotamine derivatives may induce fewer side effects than ergot-derived agents. Studies on these medications report the following:

  • 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 the most potent drug yet used for RLS and has resulted in dramatic improvement in symptoms. It seems to be very effective in improving sleep and may also reduce periodic limb movement. A long-term, follow up study showed the drug continued to be effective for RLS, even after seven months of use. Pramipexole also appears to have antidepressant properties. The drug is used at much lower doses than when used for Parkinsons disease, so severe long-term side effects are rare. However, studies have shown that tolerance (need for higher doses) and augmentation may occur in around a third of patients.
  • Ropinirole (Requip), like parmipexole, is a non-ergotamine dopamine agonist that is increasingly used for RLS treatment. Results from several large-scale clinical trials have indicated that it is effective in alleviating symptoms with few side effects.
  • Cabergoline (Dostinex) is also showing promise. 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 four weeks of use.

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), although these are not currently available in the U.S.

Regimens. L-dopa is fast acting and takes only 15 to 30 minutes before it is effective. The dopamine receptor agonists take at least two hours to become effective. Some experts then 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 agents 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 agents may eventually intensify (augments) 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 agents 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 agent 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 agents 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 RLS patients 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. They include the following:

  • 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 agents 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, and some medications, like 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 one to three weeks after stopping the drug and may include the following:

  • 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.

Potent Pain Relievers

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

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

  • Opiates, which are derived from natural opium (e.g., 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, which are synthetic drugs. The most common example is oxycodone (Percodan, Percocet, Roxicodone, Oxycontin). Apomorphine is a morphine derivative. In one study, it was administered subcutaneously (under the skin) at night and reduced nocturnal discomfort and leg movements in some patients.

Although the use of narcotics for severe RLS is controversial, many 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 agents 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 (e.g., over a year) can cause intense symptoms, including diarrhea, insomnia, and even restless legs syndrome itself.

Antiseizure Agents

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 well conducted 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 agents have potentially severe side effects and should be tried only after non-drug methods have failed. Side effects of many anti-seizure agents 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 Agents

Selective Serotonin Reuptake Inhibitors (SSRIs) and Similar Antidepressants. Imbalances in the neurotransmitter serotonin have been associated with RLS, and the common antidepressants known as SSRIs, which increase serotonin levels in the brain, may be tried. One study found that SSRIs reduced RLS in 58% of patients and eliminated symptoms in 12%. Oddly, however, RLS became worse in another 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 agents 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 apt choice for patients who have RLS accompanied by hypertension. It also appears to be helpful for RLS patients who are undergoing hemodialysis.

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

What Are Nocturnal Leg Cramps?

Benign nocturnal leg cramps, sometimes known as a charley horse, are muscle spasms in the calf that can occur one or many times during the night. Cramping may also occur in the soles of the feet. They typically last from a few seconds to a few minutes. Some people experience them regularly; others only on isolated occurrences.

Causes of Nocturnal Leg Cramps

In many cases, the cause of nocturnal leg cramps remains unknown. Among the conditions that might cause leg cramps are the following:

  • Calcium and phosphorus imbalances can cause cramping, particularly during pregnancy. Imbalances in these minerals can also occur when fluid levels in the body become low, for example from taking diuretics, excessive perspiration, vomiting, or diarrhea.
  • Low potassium or sodium (salt) levels.
  • Deficiencies of a nutrient called hesperidin, an antioxidant flavonoid found in oranges and other citrus fruits, have also been linked to nocturnal leg cramps.
  • Overexertion, standing on concrete for long periods, or prolonged sitting (especially with the legs contorted) may contribute to nighttime cramps.
  • Having structural disorders in the legs or feet (such as flat feet) may increase the risk for cramps.
  • Among the many medical causes of muscle cramping include hypothyroidism, Addisons disease, uremia, hypoglycemia, anemia, and certain medications.Various diseases, such as Parkinsons, that affect nerves and muscles cause leg cramps. Peripheral neuropathy, a complication of diabetes in which the nerves in the extremities are impaired, can cause cramp-like pain, numbness, or tingling in the legs. Patients with kidney disease undergoing dialysis are also prone to leg cramps.

Individuals at Higher Risk for Nocturnal Leg Cramps

Nocturnal leg cramps occur at all ages but peak at different times. They are particularly common in adolescence, during pregnancy, and in older age, affecting up to 70% of adults over 50 at some point.

One study in campers reported an incidence of 7.3% in children older than eight; the incidence increased at 12 years old and peaked at age 16 to 18. Most of the adolescents with leg cramps reported that they had them one to four times per year.

Pregnant women and those taking diuretics are also at risk for leg cramps because of low calcium levels and an imbalance in calcium and phosphorus.

Consequences of Nocturnal Leg Cramps

Nocturnal leg cramps, like restless legs syndrome, rarely have any serious consequences. However, they can be extremely painful and long-lasting. In some cases, severe and persistent symptoms can cause chronic insomnia and considerable mental distress.

Managing Nocturnal Leg Cramps

Once a cramp begins, straighten the leg, flex the foot upward toward the knee, or grab the toes and pull them toward the knee.

Walking or shaking the affected leg, then elevating it, may also help.

If soreness persists, a warm bath or shower or an ice pack may bring relief.

Preventing Nocturnal Leg Cramps

Lifestyle Tips. Nighttime leg cramps are generally treated with lifestyle changes.

  • Everyone with leg cramps should drink plenty of water (at least six to eight glasses daily) to maintain adequate fluid levels.
  • Pregnant women and others who get legs cramps due to low calcium levels should reduce milk intake, because drinking milk does not correct the underlying imbalances in calcium and phosphorus. Instead, they should boost calcium levels by taking nonphosphate calcium supplements.
  • To prevent cramps from occurring, nightly stretching exercises may be the best preventive measure. Patients should stand about 30 inches from a wall and, keeping the heels flat on the floor, lean forward and slowly move the hands up the wall to achieve a comfortable stretch. A few minutes on a stationary bicycle at bedtime may also help.
  • While in bed, loose covers should be used to prevent the toes and feet from pointing, which causes calf muscles to contract and cramp. Propping the feet up higher than the torso may also help.
  • During the week, swimming and water exercises are a good way to keep muscles stretched, and wearing supportive footwear is also important.

Quinine and Tonic Water. The drug quinine may provide a slight benefit for reducing the frequency of leg cramps. It had been widely used to prevent leg cramping but was banned by the FDA for over-the-counter pharmacy sales because it was reported to cause some serious, although rare, side effects, including bleeding problems and heart irregularities. Other, less serious side effects include headaches, vision problems, and rash.

Drinking tonic water before bedtime may be helpful because it contains small amounts of quinine, a substance that may help reduce cramping. The small amount of quinine found in tonic water (the amount varies by brand) is generally considered safe and may provide some benefit, although pregnant women and those with liver problems should avoid quinine in any form.

Supplements. Some small studies indicate that the mineral magnesium, taken as magnesium citrate or magnesium lactate, may provide some benefit, including in pregnant women with leg cramps.

In one small study, taking vitamin B complex was helpful. Other supplements tried for leg cramps include vitamin E, calcium, and potassium or sodium chloride, but these do not appear to be very effective. Sodium chloride (salt) may be helpful, but Western diets in general already contain excessive sodium.

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