RLS MEDICAL BULLETIN

RLS MEDICAL BULLETIN:

A PUBLICATION FOR HEALTHCARE PROVIDERS

TABLE OF CONTENTS

Introduction.........................................................................................1
Diagnosis ............................................................................................2
Treatment............................................................................................4
Specific Agents ....................................................................................9
Secondary RLS...................................................................................10
Children & RLS ..................................................................................10
References .........................................................................................11

LIST OF TABLES

Table 1. Phrases patients use to describe RLS sensations......................2
Table 2. RLS primary diagnostic criteria...............................................2
Table 3. Supportive clinical features and associated features ...............3
Table 4. Differential diagnosis of RLS ..................................................3
Table 5. Treatment algorithm for RLS...................................................5
Table 6. Rebound & augmentation.......................................................6
Table 7. Pharmacologic therapy for RLS ...............................................7
Table 8. Dosing schedule for RLS .........................................................8
Table 9. RLS diagnosis in children ......................................................11

The RLS Foundation

The Restless Legs Syndrome Foundation began in 1989 when eight people with restless legs syndrome (RLS) began sharing
letters and discussing their “rare” condition. In 1992, the Foundation was incorporated as a nonprofit organization to
address the growing need for research and information about this unknown condition. In the beginning, the Board
of Directors would gather around the kitchen table of Executive Director Pickett Guthrie to discuss their experiences
with the disease and what courses of action would provide the most relief for persons with RLS. Their goals were simple
and yet groundbreaking: increase awareness, improve treatments, and, through research, find a cure.

Today these goals have taken on a life of their own. The Foundation has grown from a handful of volunteers to a staff
of five employees in their Rochester, Minnesota office. Our understanding of RLS has also grown. We now know that the
condition is not rare at all. In fact, epidemiological research suggests that up to 7-10% of the U.S. population has
this neurologic condition.

For more information on RLS and how to become a member, visit our website at www.rls.org.

This publication has been reviewed and approved by our Medical Advisory Board. Literature distributed by the
Restless Legs Syndrome Foundation, including this bulletin, is offered for informational purposes.

Restless Legs Syndrome:
Diagnosis and Treatment in Primary Care

Introduction Patients with RLS experience a distressing urge to move the legs. RLS symptoms are
triggered by rest or inactivity and relieved or suppressed by movement.
Restless legs syndrome (RLS) is a sensorimotor disorder
characterized by a distressing urge to move the legs and in One major theory of RLS causation is that a deficiency in
some cases, other parts of the body such as the arms.1 This brain iron, particularly within dopamine-containing
urge is usually accompanied by sensory disturbances ranging neurons, may predispose to RLS.9 A link between one of
from discomfort to pain in the affected parts. RLS symptoms the genetic associations and body iron stores suggests that
most often begin during rest or inactivity and can be relieved iron metabolism may be one of the pathways influenced by
or suppressed by movement. RLS follows a circadian pattern genetic factors favoring development of RLS.7 In a current
with symptoms most intense and most easily provoked in the model of causation, brain iron deficiency leads to a dysfunction
evening and nighttime hours. RLS symptoms can range from of the dopamine pathways whose abnormal function causes
relatively mild to severe, from only rarely experienced, to an the symptoms of RLS. As far as we know, RLS is neither a
intense daily torture. When severe, RLS may have profoundly structural nor a neurodegenerative disorder, and most
disruptive effects on sleep quality and daily life. patients with RLS are neurologically normal except for
their RLS. Despite their definite response to dopaminergic
Diagnostically, RLS is considered either primary, often medications, RLS and Parkinson’s disease (PD) seem to
occurring within families, or secondary, developing in have very different underlying biologies, and there is no solid
association with other conditions (such as iron deficiency evidence that RLS can lead to PD.
anemia, pregnancy, or end-stage renal disease).
Presentation
Prevalence
Patients who have RLS may not volunteer their signs and
RLS affects 5-10% of adults in European countries and those symptoms. Healthcare providers should be alert to possible
countries whose populations originated largely in Europe.2 A study RLS in patients who complain of nocturnal leg discomfort
using conservative criteria of patients with moderately or severely or sleep disruption.
distressing RLS symptoms occurring at least twice a week yielded a
prevalence of 2.7- 4.4%.3 In the United States, RLS is believed to A single question that will be endorsed
affect more than 10 million adults4 and an estimated 1.5 million by most patients with RLS is:
children and adolescents.5 About one-third of those with RLS
symptoms are bothered sufficiently enough to seek medical When you try to relax in the evening or sleep
attention. Women seem more susceptible to RLS than men, and at night, do you ever have unpleasant, restless
most studies find that women are at least 50% more likely to have feelings in your legs that can be relieved by
RLS than men. RLS is more common in older adults although walking or movement?
it can occur as early as the pre-school years. Some studies have
suggested that in the very old, the frequency of RLS may decrease.

Etiology

RLS is believed to be a central nervous system (CNS) disorder.
It is not caused by psychiatric disorders nor by stress but may
contribute to or be exacerbated by these conditions. There is
a high frequency of familial cases of RLS, consistent with a
genetic origin in primary RLS. RLS seems to have a complex
genetic basis, but environmental factors are also important in
provoking RLS. In recent years, there have been major
genetic advances. Between 2001 and 2008, six different
linkages (RLS1-RLS6) were reported.6 In July 2007, two
groups, both working in multiple populations, reported three
associations discovered through genome-wide, case-control
association studies.7,8 The related variants may account for
more than half of all RLS. So far, it has not been possible to
determine the link between the susceptibility variants and the
biological determinations of RLS – but stay tuned! It is likely
that advances will now be rapid.

1

A patient’s description of their uncomfortable sensations will RLS Primary Diagnostic Criteria
often vary. However, common phrases used to describe the
sensations are described in Table 1. The key element is the All of the following four primary diagnostic criteria must be
urge or need to move, though some patients will emphasize present in order to support a diagnosis of RLS:
specific sensory symptoms.
• Urge to move the legs with or without dysesthesias.
Table 1. Phrases patients use to describe RLS sensations Sometimes the arms or other body parts are involved in
addition to the legs.
• “It just makes me want to move.”
• Onset or exacerbation with rest. The motor and sensory
• “It feels like I have water running underneath symptoms most often begin or worsen during periods of
my skin.” rest or inactivity, particularly when lying down or sitting.
Rest includes both lack of motor activity and decreased
• “It feels painful.” mental activation.

• “It burns and aches.” • Relief with movement. RLS symptoms are partially or
totally relieved by movements such as walking or stretching;
• “It feels like I have a toothache in my leg.” symptoms are relieved for at least as long as the activity
continues. Mental activation also reduces symptoms.
• “I have the heebie jeebies in my legs.”
• Circadian pattern. RLS symptoms usually occur or worsen
• “My legs feel creepy, crawly, and tingly.” in the evening or at bedtime. Symptoms are usually
quiescent in the morning.
• “It feels like I have worms or bugs crawling deep
in my muscles.” A simple mnemonic for these features is URGE (Table 2).

• “It feels like electricity in my legs.”

RLS patients are often unable to ride comfortably as a Supportive Clinical Features
passenger in a car or airplane for long periods of time, they
can have difficulty falling asleep or difficulty staying asleep, There are also some supportive clinical features whose
and they often suffer from fatigue, lack of concentration, presence, while not essential to a diagnosis of RLS, can help
or a depressed mood during the day.10-14 support the diagnosis:

Diagnosis • Positive family history. The frequency of RLS among first-
degree relatives of people with RLS is three to seven times
The diagnosis of RLS is based primarily upon interview with the greater than in people without RLS.20,21
patient. Currently, there are no lab tests that can definitively
confirm or deny the presence of RLS. The use of sleep studies or • Positive response to dopaminergic therapy. Nearly
a suggested immobilization test15 may occasionally be helpful in all patients with RLS show at least an initial positive
difficult cases by demonstrating the presence of periodic limb therapeutic response to either L-dopa or dopamine-receptor
movements.16 It has been proposed that response to a dopaminergic agonists. Dosages are usually considerably lower than those
medication can be formalized as a confirmatory diagnostic test.18 prescribed in the treatment of Parkinson’s disease.18,22,23
Various diagnostic instruments are under development, including
a structured interview.19 • Presence of periodic limb movements (PLM). PLM, which
occur in about 80% of people with RLS, can help confirm
Table 2. RLS primary diagnostic criteria1 a diagnosis.16,24 However, because PLM, especially those in
sleep (PLMS), are also common in some other disorders
Primary Diagnostic Criteria: URGE and among the elderly, this finding is not specific.25 Recent
genetic studies suggest that there may be a strong genetic
Urge to move the legs usually with dysesthesias connection between PLM and RLS.7 When sleep complaints
Rest induced are associated with PLMS, without RLS or any other cause
Gets better with activity for the complaints, a diagnosis of periodic limb movement
Evening or night worsening disorder (PLMD)26 can be made.

2

Table 3. Supportive clinical features and associated features These conditions, which can meet some of the diagnostic
criteria for RLS, have been called mimics.33 It is also possible
Supportive Clinical Features that RLS can co-exist with such disorders, for example,
diabetic neuropathy.34
1. Positive family history
2. Positive response to dopaminergic therapy Table 4. Differential diagnosis of RLS
3. Presence of periodic limb movements (PLM)
Disorders of Restlessness
Associated Features
• Neuroleptic-induced akathisia
1. Clinical course is generally chronic and progressive • Fidgets
2. Sleep disturbance • Semiconscious leg jiggling
3. Normal neurological exam in primary RLS, unless a • Involuntary leg movements (PLM, propriospinal

comorbid condition exists myoclonus at sleep onset, rhythmic movement disorder)26

Associated Features Disorders of Leg Discomfort

In addition to the supportive clinical features mentioned • Peripheral neuropathy
above, there are also other associated features which can help • Nocturnal leg cramps
direct the patient’s diagnosis: • Vascular or neurogenic claudication
• Pruritis
• Clinical course. The clinical course of RLS varies • Arthritic leg discomfort
considerably but is generally chronic and progressive in • Painful myopathies
patients. Onset of RLS in patients younger than 30 tends • Varicose veins or venous insufficiency
to be more insidious and may not become troublesome • Deep vein thrombosis
until middle or later age. When the age of onset is 50 years • Fasciculations
or older, symptoms often appear more abruptly.10,27,28 In
some patients, RLS can be intermittent and may remit Disorders of Both Restlessness and Leg Discomfort
spontaneously for many years.29
• Positional discomfort
• Sleep disturbance. Disturbed sleep is a common morbidity • Painful legs and moving toes
for RLS and deserves special consideration in planning
treatment.10,30 Sleep disturbance is often the primary reason Examination
a patient seeks medical attention. A sleep study is not needed
to diagnose RLS, but, if done, may show delayed sleep The physical examination in primary RLS is normal, unless
latency, excessive movement, many PLM, and disrupted there are comorbid conditions present. The examination may
sleep.31 A patient with moderate-to-severe RLS may detect secondary causes of RLS or other conditions which
average less than five hours of sleep per night and may be may be mistaken for RLS.
more sleep deprived on a chronic basis than patients with
almost any other persistent disorder of sleep. For patients The presence of a peripheral neuropathy or a radiculopathy
with mild RLS, sleep disturbance may not be a problem or may be detected during the sensory and motor components
may be a less significant issue.32 of the exam, including examination for weakness or muscle
wasting and assessment of touch, pain, vibration, and position
History and Physical Examination sense. Nerve damage may also lead to reports of painful
sensations of burning or electric-like shocks.
The history is directed towards determining whether the
patient meets the four primary diagnostic criteria and to rule Sometimes the painful sensations of peripheral neuropathy
out other disorders that share features of RLS.33 are similar to those of RLS. Moreover, the two disorders
share many common risk factors including diabetes and renal
Differential Diagnosis disease. RLS may occur with or be triggered by neuropathy,
but when RLS and neuropathy occur together, efforts should
Other disorders that may share some of the features of RLS and be made to distinguish which symptoms are from the RLS
must be ruled out are listed in Table 4. Two types of conditions and which are from the neuropathy, since treatments may vary.
are most likely to be confused with RLS: those which involve
restlessness and those which include leg discomfort.

3

Arthritis, arterial or venous disease, or other forms of local despite increasing doses;
trauma can be found by examining the leg. RLS is usually 3. intolerable adverse effects;
quiescent during examination, and the leg is not normally 4. augmentation that is not controllable with
discolored, swollen, or tender. Strength and movement
should be normal. adjustment of agonist doses.

Laboratory Evaluation Several additional recent reviews of RLS treatment are available.23, 30

There are no laboratory findings diagnostic of RLS. Because of Non-Pharmacologic Therapy
the frequent association of RLS with iron deficiency,35,36 serum
ferritin should be measured in patients with moderate or severe For patients with mild RLS, non-pharmacologic approaches
symptoms, recent exacerbation of RLS, or risk factors for low iron should be tried before prescribing medications that may have
stores. When a chronic inflammatory disorder is also present, unwanted side effects, especially in the geriatric population
transferrin saturation and TIBC should be measured as ferritin is (Table 5). Patients should follow a regular sleep schedule and
an acute phase reactant and may be falsely elevated. When iron good practices for healthy sleep (e.g., reserving bed for sleep
stores are abnormally low (serum ferritin level dependant on and intimacy, avoiding stimulant substances near bedtime,
age, gender and individual laboratory, but often <15 µg/L), iron ensuring the bedroom is quiet and dark).
repletion is indicated and a search for a cause of iron deficiency
should be undertaken. When serum ferritin levels are low normal Mild-to-moderate physical activity involving the limbs (e.g.,
(ferritin <50 µg/L), iron supplementation should be considered, stretching exercises just before bedtime), hot or cold baths, or
depending on the individual patient circumstances. Other any age-appropriate engrossing mental activity (e.g., video
laboratory tests are generally not needed unless there is clinical games, crossword puzzles) may be of value. Patients with RLS
suspicion of associated conditions such as a peripheral neuropathy can adjust their schedules to better accommodate their RLS
(when glucose and other studies may be indicated) or chronic symptoms. Sedentary activities like going to the movies or
renal failure. While a sleep study is not indicated for diagnosis taking a long airplane flight may be better suited to the
of uncomplicated RLS,37 suspicion of additional sleep problems, morning, whereas activities that require walking, such as
such as respiratory problems (for example, obstructive sleep housework or exercise, may help relieve RLS symptoms when
apnea) or sleep related violent behavior, may suggest the need performed later in the day. When traveling long distances,
for polysomnography. Electrodiagnostic tests of nerve function alerting activities or whatever movement is feasible can help
are only indicated for those patients with clinical suspicion of alleviate symptoms.
peripheral neuropathy or radiculopathy.
It is also helpful to examine other substances the patient is
The suggested immobilization test (SIT)15 is a provocative taking that may exacerbate their RLS symptoms, including
test in which the patient tries to remain still, seated in bed both over-the-counter and prescription medications (see
for about an hour, preferably in the evening when RLS Table 5). Any dopamine-blocking agents can aggravate RLS,
symptoms are most intense. The degree of discomfort is and these include almost all the neuroleptics plus many
periodically monitored and the number of PLM is measured. anti-nausea agents. Many antidepressants may aggravate RLS
The test is uncomfortable for patients and has only moderate symptoms; however, bupropion (Wellbutrin), a dopamine-
sensitivity and specificity for the diagnosis of RLS. active antidepressant, may prove to be the most preferred
antidepressant.39,40 Among over-the-counter medications,
Treatment centrally active (mostly sedating) anti-histamines may be the
greatest culprits. They are often found in over-the-counter
The first step in treating the patient diagnosed with RLS medications to treat allergies or promote sleep.
is to determine the frequency and severity of the RLS
symptoms. One treatment algorithm assigns patients to three Pharmacologic Therapy
categories reflecting increasing severity of the disorder:30,38
Pharmacologic therapy of RLS is designed to relieve the
• Intermittent RLS is RLS that is troublesome enough when patient’s sensorimotor symptoms and sleep disturbances.
present to justify treatment, but does not occur frequently Such therapy is symptomatic; it does not cure RLS but
enough to necessitate daily therapy. merely suppresses the disorder’s unwanted manifestations.
In the case of augmentation, the treatment – usually with a
• Daily RLS is RLS that is frequent and troublesome enough dopaminergic agent – may actually make the RLS worse.
to require daily therapy. This is discussed further under refractory RLS.

• Refractory RLS is daily RLS treated with at least one Curative therapy may be available to treat the underlying
dopamine agonist at usual doses with one or more of the disorder in secondary RLS, like iron deficiency or renal failure
following outcomes:
1. inability to achieve a satisfactory response;
2. response that has become unsatisfactory with time,

4

Non-Pharmacologic Table 5. Treatment algorithm for RLS Pharmacologic

Intermittent RLS

• Follow regular sleep schedule and healthy sleeping habits, • Carbidopa/levodopa, 25 mg/100 mg, or controlled-
including a trial of abstinence from caffeine and alcohol release (CR), 25 mg/100 mg
which can disrupt sleep.
• Dopamine agonists, such as pramipexole or ropinirole
• Engage in mild-to-moderate physical activity. • Low-potency opioid analgesics, such as propoxyphene,
• Try hot or cold baths to reduce symptoms.
• Recommend, as appropriate for age, mentally alerting codeine, or tramadol
• Sedative-hypnotics such as clonazepam, temazepam,
activities, such as video games or crossword puzzles.
• Schedule sedentary activities in the morning when or zolpidem*

symptoms are least bothersome.
• Stop or avoid certain drugs that can aggravate RLS

symptoms (these include many antidepressants,
neuroleptic agents, dopamine-blocking antiemetics such
as metoclopramide, and sedating anti-histamines).40,41

Daily RLS

• The non-pharmacologic approach for daily RLS is the • Approved dopamine agonists, such as pramipexole or
same as for intermittent RLS. ropinirole

• Gabapentin
• Other dopamine agonists
• Low or medium potency opioids, such as codeine

or tramadol

Refractory RLS

• Helpful non-pharmacologic approaches should be • Change to a different dopamine agonist, including those
continued in addition to pharmacologic treatment. not FDA approved for treating RLS.

• Change to an anti-convulsant such as gabapentin.
• Add a second agent such as gabapentin, a sedative-

hypnotic, or an opioid.
• Change to a high-potency opioid such as methadone,

oxycodone and hydrocodone.
• Consider rotating treatments or a drug holiday.

* Not available in Canada

(see section on “Secondary RLS” on page 10). Resolving the preventatively and cannot be used effectively once symptoms

underlying disorder may then eliminate the RLS. Pharmacologic have started. Of course, this addresses only a subset of RLS

therapy varies with the patient’s form of RLS. As of publication patients, and these two medications or other medications without

(spring 2011), the only approved medications for the treatment any approval for RLS are often used off-label to deal with dif-

of RLS are the two non-ergot dopamine agonists, ropinirole ferent clinical situations or to treat patients who cannot tolerate

(Requip, approved in the U.S. in May 2005) and pramipexole the dopamine agonists.

(Mirapex, approved in the U.S. in November 2006). Both drugs

have also been approved in Canada. They are approved only to Therapy of intermittent RLS involves the use of a wide

treat moderate-to-severe idiopathic RLS which can usually be variety of agents (Table 5) that are directed at specific problems.

managed with a single dose one to three hours before bedtime Levodopa, which causes such frequent augmentation when

(0.25 to 4 mg of ropinirole, 0.125 to 0.75 mg of pramipexole). used regularly that it is not recommended for daily treatment,

Some patients require twice-daily doses of agonists when early is often helpful for intermittent RLS. Levodopa and opioids

evening symptoms are present, typically given as an earlier dose may be useful when symptoms are unpredictable (e.g.,

in the late afternoon or early evening and a second dose before an airplane trip, a long car ride, a theatrical event, etc.)

bed. The action of dopamine agonists generally commences 90 because they do not require dose titration to be effective.

to 120 minutes after ingestion; thus, these agents must be used

5

Table 6. Rebound & augmentation

Rebound – The return of symptoms late in the night or in the morning, generally considered to be the result of
dropping drug levels.

Augmentation – An increase in RLS severity after initial response that:
1. occurs on at least 5 of 7 days at issue
2. is not accounted for by other factors (e.g., new medication, blood loss, activity change)
and occurs with either:
• “paradoxical response” with increased symptoms when dose is increased and
decreased symptoms when drug is decreased OR
• advance in time of symptoms either by (1) four hours or by (2) two hours with at
least two of the following:
a. shorter latency to symptom onset at rest
b. spread to previously unaffected body parts
c. increased intensity of symptoms or PLM
d. shorter duration of relief from treatment

Clinically significant augmentation is present when there is impact on the patient’s life indicated by a necessary medication
change, change in activities undertaken, or decreased quality of life.

Dopamine agonists need to be started with a low dose and then change to one of the non-approved agents, such as
titrated up to an effective dose to minimize side effects; therefore, alternate dopaminergics (although not levodopa), anti-
they are better for patients who need daily medication. convulsants, or opioids. Sedative-hypnotics are unlikely
to work alone in cases of refractory RLS.
When the main problem is sleep disruption (either difficulty
initiating or maintaining sleep), a sedative hypnotic may be useful. 2. Using a combination of drugs. This may allow reducing
the dosage of the primary agent to avoid adverse effects
Treatment of daily RLS should begin with titrated doses of the while adding a different drug class to permit expanded
approved agonists, ropinirole or pramipexole. The alternate agents coverage. Typical combinations have seen dopamine
should be considered as initial treatment only if there is some agonists paired with anti-convulsants, opioids, or sedative-
contra-indication or a specific clinical situation (e.g., painful RLS hypnotics. Opioids may best address waking symptoms,
with neuropathy which may be addressed with an anti-convul- while anti-convulsants and sedative-hypnotics may be
sant such as gabapentin). Non-ergot agonists are highly favored particularly useful for decreasing sleep problems.
because they seem less likely to cause a rare but potentially serious
complication of fibrosis (pleuro-pulmonary fibrosis or fibrotic 3. Considering drug holidays. In some cases, drug holidays
cardiac valvulopathy).42,43 In fact, pergolide, an ergot agonist and rotating medications have proven useful,45 but these
that was quite successful in treating RLS, has been withdrawn are difficult regimens to manage and can cause issues when
from the U.S. and Canadian markets. In the future, other stopping one agent leads to a flare up of RLS symptoms.
non-ergot agents or formulations may also be approve or
available off-label. 4. Using high potency opioid narcotics. Those patients
who have failed numerous medication regimens may be
As indicated earlier, refractory RLS can take various forms. There managed with the use of high potency opioid narcotics.
is scant medical literature on how to address these problems. The Oxycodone, hydrocodone, and methadone have been most
current recommendations, like those of the 2004 algorithm,30 are used in this situation.47
based on the clinical opinion of experts who have had much
experience in managing the more difficult cases of RLS. Augmentation

Several strategies may be useful in managing refractory RLS: Augmentation currently receives the greatest attention in cases of
refractory RLS.44 Augmentation is an iatrogenic worsening of RLS
1. Switching to a different agent. The metabolism of with one or more of the following features:45 an advance of the
ropinirole and pramipexole is different, so either may work typical time of day when symptoms begin to two or more hours
when the other has not. Alternately, it may be useful to earlier than before the start of treatment; a spread of restlessness
from the legs to the arms or trunk; a shorter interval before

6

symptoms start after adopting a quiescent position (Table 6). used to treat refractory RLS from other causes.48 All dopaminergics
Augmentation requires that the patient demonstrated at least some have the potential to cause augmentation; levodopa appears to be
initial response to medication, the exclusion of other possible a particularly frequent offender as augmentation may occur in up
causes for a worsening of symptoms, and a consistent change in to 80% of those treated with daily doses.49,50 Agonists seem to
symptoms. RLS symptoms can vary from day to day and wax and cause augmentation less frequently (probably about 22-32%) but
wane over longer time periods, so one day or just a couple of days the exact frequency remains to be determined because detection
of worsened symptoms are insufficient to diagnose augmentation. and assessment of augmentation has not yet been rigorously
applied to suitable long-term trials. While augmentation can occur
Management of augmentation follows similar approaches to those within weeks of initiating treatment, it would appear that for

Table 7. Pharmacologic therapy for RLS

Agent Advantages Disadvantages

Dopaminergic Agents Can be used on a “one time” basis or as Many patients on daily levodopa may
circumstances may require. Useful for develop augmentation. Therapeutic
Dopamine Precursors persons with intermittent RLS because effect may be reduced if taken with
• carbidopa/levodopa (Sinemet®) dopamine receptor agonists take longer high-protein food. Can cause insomnia,
• benserazide/levodopa (Madopar®) to have an effect. May also be used to sleepiness, and gastrointestinal problems.
help confirm RLS diagnosis.

Dopamine Receptor Agonists Proven to reduce subjective symptoms of Can also cause nausea and hypotension.
• pramipexole (Mirapex®) – approved RLS, decrease periodic limb movements, May cause augmentation, but less
• ropinirole (Requip®) – approved and mitigate consequences of RLS likely to do so than levodopa.
• rotigotine (Neupro®) – withdrawn symptoms. Associated with impulse control
• in the U.S. due to uneven absorption disorders.

Opioids Opioids offer an effective alternative Can cause constipation, urinary
for those whose RLS is not effectively retention, sleepiness, or cognitive
• codeine treated with dopaminergic agents. They changes. Can exacerbate obstructive
• hydrocodone (Vicodin®) can be used on an intermittent basis or sleep apnea or induce central sleep
• methadone can be used successfully for daily therapy. apnea. Tolerance and dependence
• oxycodone* (Percocet®, Wide range of potencies. possible with higher doses of stronger
agents, especially those with a
Roxicodone,® OxyContin®) shorter half-life.
• tramadol (Ultram®)
Anti-convulsants offer an effective Disadvantages vary depending on agent
Anti-convulsants alternative for those whose RLS is not but include nausea, sedation, dizziness,
effectively treated with dopaminergic dermatologic conditions, hepatic
• gabapentin (Neurontin®) agents. disorders, and bone marrow suppression.
• pregabalin (Lyrica®)
• carbamazepine (Tegretol®)

Sedative-hypnotics Sleeping aids are most effective for Can cause daytime sleepiness, gait
improving sleep quality for people who unsteadiness, and cognitive impairment,
• temazepam (Restoril®) experience the RLS symptoms at night. particularly in the elderly.
• clonazepam* (Klonopin®) May be used alone in patients intolerant
• zolpidem (Ambien®)* of dopaminergic drugs.

* Not available in Canada ** Rivotril in Canada

7

agonists, it usually begins after some months or years of daily We do not know how much of a problem augmentation will
become in the future for dopamine agonist therapy of RLS.
treatment. Augmentation with agonists may also be less severe Because the dopaminergics are so effective, they are likely
to remain the mainstays of RLS treatment for many years, despite
than with levodopa, and several clinical series have suggested it can augmentation and the development of impulse control disorders
(see page 9). No other agents have received the same degree of
be managed without completely stopping use of the agonist; most clinical testing, and no drugs from other classes, except a
experience to date has been with pramipexole.51,53 This remains to gabapentin pro-drug, are even likely to achieve FDA or European
approval for RLS within the next several years.
be proven. The only non-dopaminergic reported to cause
augmentation so far is tramadol.54

Agent Table 8. Dosing schedule for RLS Maximum Dose
Initial Dose
Carbidopa/Levodopa (Sinemet®)
Pramipexole (Mirapex®) Typical beginning doses are a half or It is not recommended to exceed a dose of
whole tablet of 25/100 (mg carbidopa/ 50/200 carbidopa/levodopa in immediate
Ropinirole (Requip®) mg levodopa) usually taken one hour or sustained release formulations, due to
before symptom onset. the risk of augmentation.
Opioids
The initial dose is typically 0.125 mg The mean effective dose from multiple
Sedative-hypnotics and is titrated upward to avoid common studies is approximately 0.375 mg.
side effects such as nausea and orthostatic Patients typically habituate to side
hypotension. effects in a matter of 7 to 10 days.
Maximum recommended dose is
0.75 mg.

The initial dose is typically 0.25 mg and The average patient responds to a total
is titrated upward every 2 to 3 days in dose in the 1.0 mg/day to 2.5 mg/day
order to avoid side effects such as nausea range. RLS patients typically habituate
and orthostatic hypotension. to side effects in a matter of 7 to 10
days. Maximum recommended dose is
4 mg/day.

• codeine 15 to 30 mg as compound • codeine 120 mg/day
• propoxyphene HCl 65 to 130 mg • propoxyphene HC 260 to 390 mg/day
• oxycodone 5 to 10 mg • oxycodone 15 to 20 mg/day
• oxycodone XR 10 mg • oxycodone XR 20 to 30 mg/day
• tramadol 50 to 100 mg • tramadol 300 to 400 mg/day
• hydrocodone 5 to 10 mg • hydrocodone 20 to 30 mg/day
• methadone 5 to 10 mg • methadone 20 to 40 mg/day

• clonazepam 0.25 mg** • clonazepam 2 mg/day
• temazepam (Restoril®) 7.5 to 1.5 mg • temazepam (Restoril®) 30mg/day
• zolpidem 5 mg* • zolpidem 20 mg/day*

Anti-convulsants • gabapentin 100 to 300 mg • gabapentin 2400 mg/day
• pregabalin 50 mg • pregabalin 450 mg/day

* Not available in Canada ** Rivotril in Canada

Maximum doses are generally reserved for patients with the most severe symptoms and are often given in multiple doses scattered
throughout the day. The recommended maxima have sometimes been exceeded cautiously depending on patient response, but all such
dosing, including for approved medications, is off-label.

8

Specific Agents agonist.55,56 There is relatively little experience with other non-
ergot agonists, but a transdermal formulation of rotigotine has
Dopaminergic Agents been shown to be effective in large-scale trials.66,67 However, the
drug been at least temporarily withdrawn from the U.S. market
Dopaminergic agents are increasingly recognized as the due to concerns about variable absorption. In Europe, there has
mainstay of pharmacologic therapy. It should be emphasized been extensive study of cabergoline for RLS,69-71 but it is difficult
to patients that the doses of dopaminergic agents used to to obtain affordable dosages in the U.S. where the drug is only
treat RLS are much lower than those used to treat Parkinson’s approved to treat pituitary adenomas. In Canada, it can also be
disease (PD), and that the most worrisome side effects with financially challenging to obtain appropriate dosages of this drug
these agents in Parkinson’s disease (e.g., dyskinesias) are rare because it is generally not covered under provincial healthcare
or non-existent in those treated for RLS. plans. In addition, it is an ergot-based agonist with a significant
tendency to cause fibrotic conditions, including cardiac
The dopamine precursor levodopa is converted to dopamine in valvulopathies.68 Lisuride has also been tested in Europe, and it
the brain. Levodopa is formulated together with a decarboxylase has been suggested that there may be less fibrosis than with other
inhibitor to prevent peripheral catabolism and reduce adverse ergot compounds due to its distinctive receptor binding.
effects due to peripheral actions (nausea, hypotension). Typical
doses are in the range of 25/100 to 50/200 (mg carbidopa/mg Opioids
levodopa) usually taken one hour before symptom onset.
Effectiveness on the first night of use at low doses supports the Opioid medications have been known to bring relief from
feasibility of intermittent or as-needed use of levodopa, as well as RLS since first described by Willis in the 17th century.72
its use in a therapeutic trial for patients in whom the diagnosis of While opioids are frequently prescribed by RLS experts, there
RLS is in doubt.18 It has typical dopaminergic side effects, which have been relatively few published reports of their use. There
include nausea, vomiting, headache, somnolence, and dizziness. It is one successful double-blind study of oxycodone73 and two
can be quite effective acutely in treating RLS, but because it so long-term clinical series indicating the usefulness of
readily causes augmentation, it is best used only for intermittent opioids.47,74 The selection of any individual opioid is based
treatment. A formulation with benserazide has been approved largely on physician preference; the addiction potential of
for use for RLS in several European countries. tramadol is low enough that it is prescribed as a non-controlled
substance in the United States. For patients with very severe,
The approved non-ergot agonists ropinirole and pramipexole nearly continuous RLS symptoms, oral methadone has been
are effective in RLS and can treat both the sensory and motor found to be useful because of its long half-life.47
symptoms (i.e., PLM).55-58 Extended release formulations of
these agonists are being developed. These agonists have the No cases of augmentation have been described with opioid use
usual dopaminergic side effects and can cause peripheral in RLS except for a small number reported for tramadol.75 Side
edema. They are associated in RLS with impulse control effects include nausea, gait unsteadiness, sedation, dizziness, and
disorders (e.g. pathologic gambling, excessive shopping, constipation. High potency opioids may induce or exacerbate
hypersexuality), with a frequency of 9-17% in prospective obstructive or central sleep apnea. There are also concerns about
studies. This complication develops a mean of 10 months abuse potential, addiction, and practical problems (e.g., transfer
after treatment onset, so it it is essential to repeatedly warn to non-patients when medications are not secure) arising from
patients and inquire about symptoms at each subsequent visit. the use of “controlled” drugs, and prescribers need to be sensitive
The consequences of unrecognized impulse control disorders to such issues. As a result, many physicians and patients are not
can be devastating, including serious financial loss and criminal comfortable using narcotic medications to treat a long-term
prosecutions. However, complete resolution of the pathologic condition. Nevertheless, opioids often provide significant relief
tendencies is the general rule with discontinuation of the for RLS when other treatments have failed and may represent
causative agent.59-61 There is evidence that somnolence, including the optimum treatment for some patients.
sleep attacks, is more common in Parkinson’s disease (PD)
patients taking these agonists65 but to date this has not been a Anti-Convulsants
major problem in treating RLS.62-64
The most experience in RLS has been with gabapentin, which
The typical PD phenomena of fluctuations, dyskinesias, has shown promise in the treatment of RLS and associated sleep
hallucinations, and psychosis have at most been rare problems for disturbance.76 Gabapentin is generally well tolerated but can
RLS patients, perhaps because of the different biology and lower cause sedation, dizziness, and unsteadiness, especially in older
doses used. Augmentation does occur fairly frequently over the individuals. It has been tested in head-to-head trials against
long term, but the evidence to date indicates that, at least in dopaminergics with generally comparable results,77,78 but
expert hands, it is often manageable without withdrawing the overall experience is less extensive. Gabapentin has less drug-
drug interactions due to its renal route of excretion. It may be
particularly well suited for individuals with comorbid RLS and

9

peripheral neuropathy, and it is often used as an adjunctive agent Pregnancy
in RLS with persistent sleep disturbance due to its mild sedative
properties. Pregabalin,79 a related compound, has been shown in RLS also frequently occurs initially or is exacerbated during
a controlled trial to be effective in managing RLS. A gabapentin pregnancy. New-onset RLS generally appears in the last
pro-drug, gabapentin enacarbil, has also been shown to be trimester and clears with delivery. The cause of the increased
effective, but has not been approved for use in the U.S.80 incidence of RLS during pregnancy remains uncertain. While
having been pregnant may be a risk factor for later RLS,87 we
Sedative-Hypnotics do not yet know whether those who develop RLS during
pregnancy are also at increased risk for later RLS. Treatment
Benzodiazepines (particularly clonazepam**) have been of RLS in pregnant women is hampered by the limited
extensively used for evening and nocturnal RLS due to information about which drugs are safe during pregnancy.
their ability to induce and maintain sleep; however, their Pregnant women are often iron deficient and may benefit
therapeutic effects in this condition have not been extensively from iron supplementation. For more information, please see
studied. The recent development of dopaminergic agents the separate booklet, Pregnancy and RLS: Vital considerations
with improved symptom relief has relegated benzodiazepines in treating a pregnant patient who has restless legs syndrome
to second-line status or when insomnia persists after elimination (RLS), which can be downloaded at www.rls.org/publications.
of RLS symptoms. Clonazepam** was found very effective
and well tolerated in a long-term study of sleep-disrupted Iron Deficiency
patients.81 However, this longer acting agent has a higher
frequency of daytime somnolence and cognitive disturbance Serum levels of ferritin, the primary storage unit for iron, have been
(5-15%) than sedative-hypnotic drugs with shorter durations found to correlate inversely with RLS severity.35,36 The lower the
of action (but even less evidentiary support), such as iron level and the more acute the onset of symptoms, the more
temazepam and zolpidem.* Another factor to consider is that likely it is that improvement can be expected in RLS symptoms
clonazepam** is available as a generic with quite modest cost with iron supplements. The value of raising ferritin levels much
to the patient. As with opioids, careful screening for past above 50 µg/L remains unclear. Iron treatment can be instituted
drug or alcohol misuse, abuse, or dependency is important, with ferrous sulfate, 325 mg three times a day with 500 mg of
and close monitoring is necessary. vitamin C (to acidify the stomach and promote absorption) or
comparable doses of elemental iron. Intravenous iron improved
Secondary RLS RLS in open label trials88,89 but failed to do so in one double-blind
trial using an iron sucrose infusion.90 Given the need to consider
End-Stage Renal Disease (ESRD) different formulations and establish RLS benefit, this treatment
should be restricted to patients with a diagnosis of definite iron
It has been recognized for over 40 years that, in comparison insufficiency who have malabsorption states preventing oral iron
to the general population, RLS is more common in individuals absorption or complete intolerance to oral iron preparations. With
with ESRD both before and after the institution of dialysis. the institution of oral iron supplementation, serum ferritin levels
Recent prevalence studies indicate that the rates of RLS and percent transferrin saturation (%sat) should be checked at
among this patient group range from 6-83%, varying with intervals not longer than every three months. Supplemental iron
racial groups and with modes of management. Both RLS and may be discontinued once the patient’s serum ferritin level reaches
a PLM index greater than 20 are significant independent 50 µg/L and should not be continued if %sat >50% given the risks
predictors of mortality in this population.82,83 Quality of life of hemochromatosis.91 Low ferritin or anemia may also be a sign of
is also adversely affected.84,85 bleeding and may indicate the need for a workup. RLS has been
the presenting symptom of colon cancer.92
The causes of the high prevalence of RLS in ESRD remain
to be fully described. Anemia has been linked to RLS, and Children & RLS
normalization of hematocrit with recombinant erythropoietin
has resulted in a significant reduction in PLM.83 Most general Recent literature reveals that RLS occurs more frequently in
RLS medications work in uremia, though doses and their children than previously recognized.4 Young children present
timing may need to be adjusted to compensate for kidney a diagnostic challenge since many symptoms of RLS are
failure. Transplantation, but not dialysis, improves and subjective and difficult to explain, even for adults. A
sometimes cures RLS in uremia. workshop at the National Institutes of Health (NIH) in May
2002 resulted in specific consensus criteria for the diagnosis
*Not available in Canda **Rivotril in Canada of pediatric RLS.1 Mindful of the diagnostic challenge,
participants and experts in the NIH-sponsored workshop
intentionally made it difficult to arrive at a definite RLS
diagnosis in childhood. Probable and possible RLS categories

10

Table 9. RLS diagnosis in children deficit/hyperactivity disorder (ADHD)) and oppositional
behaviors (oppositional defiant disorder), may be more
Definite RLS common in these children.97,98 Further research is needed to
understand the association of these disorders with RLS and
1. The child meets all four essential adult criteria PLMS; a possible biologic basis may lie in iron deficiency in
for RLS, and children which has been associated both with RLS and ADHD.99-101

2. The child relates a description in his or her own words Treatment
that is consistent with leg discomfort. (The child may
use terms such as oowies, tickle, spiders, boo-boos, There are limited investigations of treatment for RLS in the
want to run, and a lot of energy in my legs to describe pediatric population. Most “evidence” is gleaned from a few
symptoms. Age-appropriate descriptors are encouraged.) case reports and two case series of children with RLS and/or
periodic limb movement disorder (PLMD). The case reports
OR have indicated individual responses to strict limit-setting to
promote a good sleep schedule, restriction of caffeine, iron
1. The child meets all four essential adult criteria for supplementation, and medications such as clonazepam,
RLS, and carbidopa/levodopa, pergolide, pramipexole, ropinirole, and
clonidine.102,103 In children with iron deficiency (as determined
2. Two of three supportive criteria are present: by measurement of serum ferritin levels), therapy to correct
a. Sleep disturbance for age. the iron deficit can successfully relieve RLS symptoms. As to
b. A biologic parent or sibling has definite RLS. safety in children, medications such as benzodiazepines, anti-
c. The child has a polysomno-graphically convulsants, alpha-adrenergic agents, and opioids have been
documented periodic limb movement index used extensively in children with disorders other than RLS, as
of 5 or more per hour of sleep. has chronic use of levodopa for dopa-responsive dystonia.104
In a small open-label trial of dopaminergic medication used
were developed to promote research in this area. For more in six children with RLS and ADHD, an improvement was
information, please see the RLS Foundation’s Children and demonstrated in RLS symptoms and sleep, as well as in
RLS: Restless Legs Syndrome and Periodic Leg Movement scores of attention and impulsivity.102 In association with any
Disorder in Children and Adolescents: A Guide for Healthcare medical therapy for RLS, it is implicit that interventions for
Providers available for download at www.rls.org/publications. behavioral-, sleep schedule-, and sleep hygiene-related problems
occur before or in coordination with the medical therapy.
Diagnosis in Children
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provider. Literature concerning RLS that is distributed by the
81. Schenck CH, Mahowald MW. Long-term, nightly benzodiazepine treatment of Restless Legs Syndrome Foundation, Inc., is offered for information
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