US Pharm. 2014;39(1):8-11.
Restless legs syndrome (RLS), also known as nocturnal myoclonus, is a neurologic disorder.1 It is referred to as a movement disorder
since patients feel a compulsion to continually move their legs to
relieve their discomfort. Those with RLS may ask pharmacists what steps
they should take to manage the condition.
Prevalence of RLS
RLS is thought to affect about 10% of the U.S. population.1
Perhaps half of these have only a mild form. Another 2% to 3% of adults
experience moderate-to-severe RLS. Approximately 1 million children of
school age have RLS, and one-third of those have the moderate-to-severe
form.1 The true prevalence is underreported, as many patients
do not seek medical care, feeling that the condition cannot be treated,
that their physician will not take them seriously, and/or that their
symptoms are too mild to trouble a prescriber.1
Epidemiology of RLS
Both genders experience RLS, but the ratio in women to men is 2 to 1.1 Although it can occur at any age, the peak age of onset is middle age and above.1 RLS symptoms increase in severity and duration of attack as the patient ages.1 Stress and emotional upset can worsen the symptoms of RLS, and sleep deprivation may be causal.
Etiology of RLS
In the majority of cases, the cause of RLS is not known.
Preliminary evidence suggests that some RLS sufferers have lower levels
of iron in the brain, but iron supplementation is not considered to be
an effective therapeutic option.1
Researchers have identified a possible physiological basis for RLS.1
Dopamine is necessary for the successful use of muscles to produce
purposeful movement. As in Parkinson’s disease, the brain’s ability to
use dopamine is thought to be disrupted, causing the involuntary
movements seen with Parkinson’s, and perhaps also the discomfort of RLS.
The two conditions commonly coexist, lending further credence to this
RLS may be an adverse reaction to such drugs as caffeine, calcium channel blockers, lithium, and neuroleptics.2 It may occur when the sedative dosages are being tapered or discontinued, and may also occur with use of alcoholic beverages.
RLS appears to have a genetic basis; when this is the
case, symptoms begin when the paient is younger (i.e., below the age of
40 years).2 Despite this presumed association, RLS has not
yet been pinned to a causative genetic defect, although specific gene
variants are associated with the disorder.1,2
Symptoms similar to RLS occur in the presence of certain
medical conditions, although none is proven to cause RLS. For instance,
chronic diseases such as kidney failure, diabetes mellitus, and
peripheral neuropathy produce uncomfortable RLS-like symptoms, and
successful treatment of the underlying disorder usually allows the
symptoms to subside.1,2 Similarly, pregnant patients report
RLS, especially during the last trimester. It usually resolves within a
month or so of delivery.
Manifestations of RLS
Symptoms of RLS most often occur in the lower legs, above
the ankle but below the knee; some patients experience RLS in the upper
leg, although this is far less common.2 While the name
“restless legs” implies that the disease is limited to the legs,
patients occasionally report similar discomfort in the trunk, head,
feet, or arms.1,2
RLS symptoms are a type of paresthesia or dysesthesia.1 Sufferers describe RLS symptoms that range from mildly uncomfortable or moderately irritating to extremely painful.1 They appear to be a combination of throbbing, aching, creeping, crawling, pulling, searing, tingling, and/or bubbling feelings.2
These feelings are so uncomfortable that it is difficult to ignore
them, and some relief is obtained by moving the legs to a new position.
Such relief is transitory, however, and within a few seconds there is an
urge to try another position in the quest to gain comfort. These
sensations can last for an hour or longer, slowly increasing in
severity.1,2 While the sensations are most often bilateral, some patients experience them only on one side of the body.
The most common time for RLS to occur is at night when the
person lies down to sleep. Patients usually enjoy a symptom-free period
in the early morning. Thus, they may be able to obtain a refreshing
stretch of sleep during this time. Occasionally, patients experience RLS
during the day when they try to rest or relax, or when they are forced
to assume a fixed position for a prolonged time, such as when watching a
movie in a theater, traveling in a car or plane for a long period, or
being immobilized in a cast.
Symptoms of RLS vary in severity and frequency from
patient to patient. While there is a definite trend for the symptoms to
worsen with the passage of time, the speed at which this occurs varies
with the underlying cause of the RLS. If the RLS is associated with (or
caused by) another medical condition, symptoms generally progress more
rapidly. RLS that is not associated with another medical condition
advances more slowly in severity.
There are three defined levels of severity with RLS.1
The mildest form causes some disruption in onset of sleep, but its
interference with daytime activities is only of a minor nature. When the
condition is moderately severe, patients experience RLS once or twice
weekly, with a significant disruption of sleep onset and a more
pronounced disruption of daytime functioning.
Severe RLS is characterized by symptoms on more than 2
days each week, causing severe disruption of sleep; daytime function
becomes impaired beyond anything in lesser levels of severity.
Patients may notice that symptoms wax and wane, especially in the early stages of RLS.1
They may ebb to the point where they are no longer noticeable to any
degree, and this spontaneous remission can last as long as weeks to
At least 80% of patients with RLS also have a condition known as periodic limb movements, in which the limbs twitch or jerk during sleep, sometimes in repetitive, rhythmic patterns.1,2 The movements often repeat at 15- to 40-second intervals.
Diagnosis of RLS
Physicians may misdiagnose RLS as simple muscle cramps
and/or wrongly attribute the symptoms to aging, nervousness, insomnia,
stress, or arthritis. RLS cannot presently be diagnosed by a specific
confirmatory examination or test. Physical examinations and laboratory
tests seldom find any abnormality. However, they may uncover peripheral
nerve disease and conditions with similar symptoms, such as iron
Sequelae of RLS
True RLS is not secondary to a more serious condition,
although some conditions cause similar manifestations (e.g., peripheral
neuropathy). RLS is neither dangerous nor life-threatening. RLS disrupts
sleep (perhaps to the point of overt insomnia) because of the need to
move the legs, and that can have consequences that range from trivial to
deadly. The patient may fall asleep during class or while watching
television. On a more severe level, jobs, personal relationships, and
activities of daily living may suffer.
Lack of sleep can also cause depression, impaired memory, poor concentration, and inability to accomplish daily tasks.2
If sleep deprivation during the night causes the patient to fall asleep
while driving, the risk of killing oneself and other drivers cannot be
Treatment of RLS
Relief of RLS can be attained by moving the legs when
lying down, but if the patient has not yet gone to bed, pacing or
walking may help.1 Early treatment of RLS focuses on reducing
stress and emotional upset. Patients may also be advised to attempt
nonpharmacologic options, such as gentle stretching exercises, massage,
heat therapy, cryotherapy, and warm baths.
Patients with mild-to-moderate symptoms may gain relief through elimination of alcohol, tobacco, and caffeine.1
Supplements with iron, folate, and magnesium can correct deficiencies
that may contribute to RLS. Patients should be urged to adopt a regular
sleeping and awakening pattern. While any of the nonpharmacologic
measures listed may give limited relief, none can totally eliminate RLS
whether singly or in combination.
Treatment of RLS can be directed through the use of
several algorithms, but this review will discuss some of the most
commonly used medications, the dopaminergic group.3,4
Drugs that increase brain dopamine levels are useful in Parkinson’s disease and are considered the treatment of choice for RLS.2 Three medications have been approved by the FDA for treatment of moderate-to-severe RLS.
Pramipexole (Mirapex) is useful for RLS, in a dose of 0.125 mg taken once daily, 2 to 3 hours before retiring.5
If symptoms do not remit, the dosage may be increased to 0.25 mg daily
after 4 to 7 days, and increased again to 0.5 mg after another 4 to 7
days with inadequate relief of symptoms. The most common adverse effects
in patients taking pramipexole for RLS are headache and nausea. Taking
the tablet with food may prevent nausea. Patients should abstain from
alcohol while using it and should take precautions while driving,
operating machinery, or engaging in dangerous hobbies until they know
how it affects them. Patients should be warned of the risk of suddenly
falling asleep without warning during normal daily activities such as
driving. They may also experience hallucinations.5
Ropinirole (Requip) is also indicated for RLS, with a dose of 0.25 mg, taken 1 to 3 hours prior to bedtime.6
The dosage can be increased to 0.5 mg after 2 days, and to 1 mg after
the first full week of dosing. The most common adverse effects in those
taking it for RLS are nausea, vomiting, dizziness, and drowsiness.
Patients may also fall asleep without warning during normal daily
activities and may also experience hallucinations.6
Rotigotine transdermal patch (Neupro) is FDA-approved for RLS.7
Patients are instructed to apply the patch once daily. This product
also carries the warning regarding sudden sleep events, but further
cautions patients not to wear the patch during an MRI to prevent skin
burns. Patients should avoid exposing the patch to heating pads,
electric blankets, heated waterbeds, heat lamps, hot tubs, saunas, and
direct sunlight, as it could release excessive amounts of the drug.7
Who Suffers From Restless Legs Syndrome (RLS)?
RLS is not common in young people. Instead, it is most
often seen in middle-aged and older adults. The condition may have a
genetic basis, so parents and children in the same families often have
it. When this is the case, the age of onset is sometimes younger. RLS is
more common in patients who have chronic kidney disease, iron
deficiency, Parkinson’s disease, diabetes, or peripheral neuropathy, and
in those who are pregnant. RLS may also occur in patients withdrawing
from sedatives or in those using caffeine, calcium channel blockers for
high blood pressure, or lithium for bipolar disorder.
What Are the Symptoms of RLS?
RLS produces a set of uncomfort-able sensations, most
often in the area of the leg above the ankle but below the knee. Other
possible locations include the upper legs, feet, and arms. The
discomfort can start during the day when you have been sitting for a
long period of time, or at night when you lie down to sleep. It may
subside after an hour or so, but it may be present for so long that
sleep is disrupted. The discomfort of RLS can be described as an aching,
creeping, tingling, crawling, pulling, searing, or bubbling sensation.
The Effects of RLS
RLS is not dangerous, nor is it life-threatening. It is
not a sign that you have cancer, diabetes, or any other more serious
medical condition. However, it can cause you to lose sleep. Sleep
disruption can lead to daytime drowsiness, increasing the risk of
accidents while driving or working the following day and possibly
causing anxiety, depression, confusion, or slowed thought processes. In
addition to sleep disruption, RLS can make it uncomfortable to sit still
while traveling in a plane, boat, or car. Sitting through classes or
business meetings can be a challenge too.
In many cases, RLS can be alleviated by moving the legs,
standing, or walking. Stress seems to worsen RLS in some people, so any
stress relief that can be instituted (e.g., exercising regularly) may
help stop RLS. Since caffeine can cause or worsen RLS, patients are
advised to halt all caffeine intake to see whether total avoidance
There are no nonprescription products or supplements that
can help with RLS, but prescription medications (dopaminergic agents)may
provide relief. Your physician has several choices of effective drugs,
including oral tablets/capsules and a transdermal patch. You should
closely follow all directions given by your physician and pharmacist.
Some of the most commonly used drugs may cause you to fall asleep
suddenly and without warning, even while driving or performing other
activities of daily living. Watch closely for this problem. It may be
wise to have another person drive you during the first few weeks of
using the new medication. Avoid alcohol as well while taking it.
Remember, if you have questions, Consult Your Pharmacist.
1. Restless legs syndrome fact sheet. National Institute
of Neurological Disorders and Stroke.
Accessed November 25, 2013.
2. Restless legs syndrome. MedlinePlus. www.nlm.nih.gov/medlineplus/ency/article/000807.htm. Accessed November 25, 2013.
3. Silber MH, Becker PM, Earley C, et al. Willis-Ekbom
Disease Foundation revised consensus statement on the management of
restless legs syndrome. Mayo Clin Proc. 2013;88:977-986.
4. Willis-Ekbom disease: causes, diagnosis and treatment.
Willis-Ekbom Disease Foundation. www.rls.org/document.doc?id=2323.
Accessed November 25, 2013.
5. Mirapex (pramipexole dihydrochloride) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; August 2013.
6. Requip (ropinirole tablets) package insert. Research Triangle Park, NC: GlaxoSmithKline; May 2009.
7. Using the Neupro Patch. UCB, Inc. www.neupro.com/restless-legs-syndrome/how-neupro-works.aspx. Accessed November 25, 2013.
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