rls medical bulletin - Restless Legs Syndrome Foundation

rls medical bulletin - Restless Legs Syndrome Foundation

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
Restless legs syndrome (RLS) is a sensorimotor disorder
characterized by a distressing urge to move the legs and in
some cases, other parts of the body such as the arms.1 This
urge is usually accompanied by sensory disturbances ranging
from discomfort to pain in the affected parts. RLS symptoms
most often begin during rest or inactivity and can be relieved
or suppressed by movement. RLS follows a circadian pattern
with symptoms most intense and most easily provoked in the
evening and nighttime hours. RLS symptoms can range from
relatively mild to severe, from only rarely experienced, to an
intense daily torture. When severe, RLS may have profoundly
disruptive effects on sleep quality and daily life.
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.
Diagnostically, RLS is considered either primary, often
occurring within families, or secondary, developing in
association with other conditions (such as iron deficiency
anemia, pregnancy, or end-stage renal disease).
One major theory of RLS causation is that a deficiency in
brain iron, particularly within dopamine-containing
neurons, may predispose to RLS.9 A link between one of
the genetic associations and body iron stores suggests that
iron metabolism may be one of the pathways influenced by
genetic factors favoring development of RLS.7 In a current
model of causation, brain iron deficiency leads to a dysfunction
of the dopamine pathways whose abnormal function causes
the symptoms of RLS. As far as we know, RLS is neither a
structural nor a neurodegenerative disorder, and most
patients with RLS are neurologically normal except for
their RLS. Despite their definite response to dopaminergic
medications, RLS and Parkinson’s disease (PD) seem to
have very different underlying biologies, and there is no solid
evidence that RLS can lead to PD.
Prevalence
RLS affects 5-10% of adults in European countries and those
countries whose populations originated largely in Europe.2 A study
using conservative criteria of patients with moderately or severely
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
affect more than 10 million adults4 and an estimated 1.5 million
children and adolescents.5 About one-third of those with RLS
symptoms are bothered sufficiently enough to seek medical
attention. Women seem more susceptible to RLS than men, and
most studies find that women are at least 50% more likely to have
RLS than men. RLS is more common in older adults although
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.
Presentation
Etiology
Patients who have RLS may not volunteer their signs and
symptoms. Healthcare providers should be alert to possible
RLS in patients who complain of nocturnal leg discomfort
or sleep disruption.
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.
A single question that will be endorsed
by most patients with RLS is:
When you try to relax in the evening or sleep
at night, do you ever have unpleasant, restless
feelings in your legs that can be relieved by
walking or movement?
1
RLS Primary Diagnostic Criteria
A patient’s description of their uncomfortable sensations will
often vary. However, common phrases used to describe the
sensations are described in Table 1. The key element is the
urge or need to move, though some patients will emphasize
specific sensory symptoms.
All of the following four primary diagnostic criteria must be
present in order to support a diagnosis of RLS:
• Urge to move the legs with or without dysesthesias.
Sometimes the arms or other body parts are involved in
addition to the legs.
Table 1. Phrases patients use to describe RLS sensations
• Onset or exacerbation with rest. The motor and sensory
symptoms most often begin or worsen during periods of
rest or inactivity, particularly when lying down or sitting.
Rest includes both lack of motor activity and decreased
mental activation.
• “It just makes me want to move.”
• “It feels like I have water running underneath
my skin.”
• “It feels painful.”
• Relief with movement. RLS symptoms are partially or
totally relieved by movements such as walking or stretching;
symptoms are relieved for at least as long as the activity
continues. Mental activation also reduces symptoms.
• “It burns and aches.”
• “It feels like I have a toothache in my leg.”
• “I have the heebie jeebies in my legs.”
• “My legs feel creepy, crawly, and tingly.”
• “It feels like I have worms or bugs crawling deep
in my muscles.”
• Circadian pattern. RLS symptoms usually occur or worsen
in the evening or at bedtime. Symptoms are usually
quiescent in the morning.
• “It feels like electricity in my legs.”
A simple mnemonic for these features is URGE (Table 2).
Supportive Clinical Features
RLS patients are often unable to ride comfortably as a
passenger in a car or airplane for long periods of time, they
can have difficulty falling asleep or difficulty staying asleep,
and they often suffer from fatigue, lack of concentration,
or a depressed mood during the day.10-14
There are also some supportive clinical features whose
presence, while not essential to a diagnosis of RLS, can help
support the diagnosis:
Diagnosis
• Positive family history. The frequency of RLS among firstdegree relatives of people with RLS is three to seven times
greater than in people without RLS.20,21
The diagnosis of RLS is based primarily upon interview with the
patient. Currently, there are no lab tests that can definitively
confirm or deny the presence of RLS. The use of sleep studies or
a suggested immobilization test15 may occasionally be helpful in
difficult cases by demonstrating the presence of periodic limb
movements.16 It has been proposed that response to a dopaminergic
medication can be formalized as a confirmatory diagnostic test.18
Various diagnostic instruments are under development, including
a structured interview.19
• Positive response to dopaminergic therapy. Nearly
all patients with RLS show at least an initial positive
therapeutic response to either L-dopa or dopamine-receptor
agonists. Dosages are usually considerably lower than those
prescribed in the treatment of Parkinson’s disease.18,22,23
• Presence of periodic limb movements (PLM). PLM, which
occur in about 80% of people with RLS, can help confirm
a diagnosis.16,24 However, because PLM, especially those in
sleep (PLMS), are also common in some other disorders
and among the elderly, this finding is not specific.25 Recent
genetic studies suggest that there may be a strong genetic
connection between PLM and RLS.7 When sleep complaints
are associated with PLMS, without RLS or any other cause
for the complaints, a diagnosis of periodic limb movement
disorder (PLMD)26 can be made.
Table 2. RLS primary diagnostic criteria1
Primary Diagnostic Criteria: URGE
Urge to move the legs usually with dysesthesias
Rest induced
Gets better with activity
Evening or night worsening
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
that RLS can co-exist with such disorders, for example,
diabetic neuropathy.34
Supportive Clinical Features
Table 4. Differential diagnosis of RLS
1. Positive family history
2. Positive response to dopaminergic therapy
3. Presence of periodic limb movements (PLM)
Associated Features
Disorders of Restlessness
1. Clinical course is generally chronic and progressive
2. Sleep disturbance
3. Normal neurological exam in primary RLS, unless a
comorbid condition exists
• Neuroleptic-induced akathisia
• Fidgets
• Semiconscious leg jiggling
• Involuntary leg movements (PLM, propriospinal
myoclonus at sleep onset, rhythmic movement disorder)26
Associated Features
Disorders of Leg Discomfort
In addition to the supportive clinical features mentioned
above, there are also other associated features which can help
direct the patient’s diagnosis:
• Peripheral neuropathy
• Nocturnal leg cramps
• Vascular or neurogenic claudication
• Pruritis
• Arthritic leg discomfort
• Painful myopathies
• Varicose veins or venous insufficiency
• Deep vein thrombosis
• Fasciculations
• Clinical course. The clinical course of RLS varies
considerably but is generally chronic and progressive in
patients. Onset of RLS in patients younger than 30 tends
to be more insidious and may not become troublesome
until middle or later age. When the age of onset is 50 years
or older, symptoms often appear more abruptly.10,27,28 In
some patients, RLS can be intermittent and may remit
spontaneously for many years.29
Disorders of Both Restlessness and Leg Discomfort
• Positional discomfort
• Painful legs and moving toes
• Sleep disturbance. Disturbed sleep is a common morbidity
for RLS and deserves special consideration in planning
treatment.10,30 Sleep disturbance is often the primary reason
a patient seeks medical attention. A sleep study is not needed
to diagnose RLS, but, if done, may show delayed sleep
latency, excessive movement, many PLM, and disrupted
sleep.31 A patient with moderate-to-severe RLS may
average less than five hours of sleep per night and may be
more sleep deprived on a chronic basis than patients with
almost any other persistent disorder of sleep. For patients
with mild RLS, sleep disturbance may not be a problem or
may be a less significant issue.32
Examination
The physical examination in primary RLS is normal, unless
there are comorbid conditions present. The examination may
detect secondary causes of RLS or other conditions which
may be mistaken for RLS.
The presence of a peripheral neuropathy or a radiculopathy
may be detected during the sensory and motor components
of the exam, including examination for weakness or muscle
wasting and assessment of touch, pain, vibration, and position
sense. Nerve damage may also lead to reports of painful
sensations of burning or electric-like shocks.
History and Physical Examination
The history is directed towards determining whether the
patient meets the four primary diagnostic criteria and to rule
out other disorders that share features of RLS.33
Sometimes the painful sensations of peripheral neuropathy
are similar to those of RLS. Moreover, the two disorders
share many common risk factors including diabetes and renal
disease. RLS may occur with or be triggered by neuropathy,
but when RLS and neuropathy occur together, efforts should
be made to distinguish which symptoms are from the RLS
and which are from the neuropathy, since treatments may vary.
Differential Diagnosis
Other disorders that may share some of the features of RLS and
must be ruled out are listed in Table 4. Two types of conditions
are most likely to be confused with RLS: those which involve
restlessness and those which include leg discomfort.
3
despite increasing doses;
3. intolerable adverse effects;
4. augmentation that is not controllable with
adjustment of agonist doses.
Arthritis, arterial or venous disease, or other forms of local
trauma can be found by examining the leg. RLS is usually
quiescent during examination, and the leg is not normally
discolored, swollen, or tender. Strength and movement
should be normal.
Laboratory Evaluation
Several additional recent reviews of RLS treatment are available.23, 30
Non-Pharmacologic Therapy
There are no laboratory findings diagnostic of RLS. Because of
the frequent association of RLS with iron deficiency,35,36 serum
ferritin should be measured in patients with moderate or severe
symptoms, recent exacerbation of RLS, or risk factors for low iron
stores. When a chronic inflammatory disorder is also present,
transferrin saturation and TIBC should be measured as ferritin is
an acute phase reactant and may be falsely elevated. When iron
stores are abnormally low (serum ferritin level dependant on
age, gender and individual laboratory, but often <15 µg/L), iron
repletion is indicated and a search for a cause of iron deficiency
should be undertaken. When serum ferritin levels are low normal
(ferritin <50 µg/L), iron supplementation should be considered,
depending on the individual patient circumstances. Other
laboratory tests are generally not needed unless there is clinical
suspicion of associated conditions such as a peripheral neuropathy
(when glucose and other studies may be indicated) or chronic
renal failure. While a sleep study is not indicated for diagnosis
of uncomplicated RLS,37 suspicion of additional sleep problems,
such as respiratory problems (for example, obstructive sleep
apnea) or sleep related violent behavior, may suggest the need
for polysomnography. Electrodiagnostic tests of nerve function
are only indicated for those patients with clinical suspicion of
peripheral neuropathy or radiculopathy.
For patients with mild RLS, non-pharmacologic approaches
should be tried before prescribing medications that may have
unwanted side effects, especially in the geriatric population
(Table 5). Patients should follow a regular sleep schedule and
good practices for healthy sleep (e.g., reserving bed for sleep
and intimacy, avoiding stimulant substances near bedtime,
ensuring the bedroom is quiet and dark).
Mild-to-moderate physical activity involving the limbs (e.g.,
stretching exercises just before bedtime), hot or cold baths, or
any age-appropriate engrossing mental activity (e.g., video
games, crossword puzzles) may be of value. Patients with RLS
can adjust their schedules to better accommodate their RLS
symptoms. Sedentary activities like going to the movies or
taking a long airplane flight may be better suited to the
morning, whereas activities that require walking, such as
housework or exercise, may help relieve RLS symptoms when
performed later in the day. When traveling long distances,
alerting activities or whatever movement is feasible can help
alleviate symptoms.
It is also helpful to examine other substances the patient is
taking that may exacerbate their RLS symptoms, including
both over-the-counter and prescription medications (see
Table 5). Any dopamine-blocking agents can aggravate RLS,
and these include almost all the neuroleptics plus many
anti-nausea agents. Many antidepressants may aggravate RLS
symptoms; however, bupropion (Wellbutrin), a dopamineactive antidepressant, may prove to be the most preferred
antidepressant.39,40 Among over-the-counter medications,
centrally active (mostly sedating) anti-histamines may be the
greatest culprits. They are often found in over-the-counter
medications to treat allergies or promote sleep.
The suggested immobilization test (SIT)15 is a provocative
test in which the patient tries to remain still, seated in bed
for about an hour, preferably in the evening when RLS
symptoms are most intense. The degree of discomfort is
periodically monitored and the number of PLM is measured.
The test is uncomfortable for patients and has only moderate
sensitivity and specificity for the diagnosis of RLS.
Treatment
The first step in treating the patient diagnosed with RLS
is to determine the frequency and severity of the RLS
symptoms. One treatment algorithm assigns patients to three
categories reflecting increasing severity of the disorder:30,38
Pharmacologic Therapy
• Intermittent RLS is RLS that is troublesome enough when
present to justify treatment, but does not occur frequently
enough to necessitate daily therapy.
Pharmacologic therapy of RLS is designed to relieve the
patient’s sensorimotor symptoms and sleep disturbances.
Such therapy is symptomatic; it does not cure RLS but
merely suppresses the disorder’s unwanted manifestations.
In the case of augmentation, the treatment – usually with a
dopaminergic agent – may actually make the RLS worse.
This is discussed further under refractory RLS.
• Daily RLS is RLS that is frequent and troublesome enough
to require daily therapy.
• Refractory RLS is daily RLS treated with at least one
dopamine agonist at usual doses with one or more of the
following outcomes:
1. inability to achieve a satisfactory response;
2. response that has become unsatisfactory with time,
Curative therapy may be available to treat the underlying
disorder in secondary RLS, like iron deficiency or renal failure
4
Non-Pharmacologic
Table 5. Treatment algorithm for RLS
Intermittent RLS
Pharmacologic
• Follow regular sleep schedule and healthy sleeping habits,
including a trial of abstinence from caffeine and alcohol
which can disrupt sleep.
• Engage in mild-to-moderate physical activity.
• Try hot or cold baths to reduce symptoms.
• Recommend, as appropriate for age, mentally alerting
activities, such as video games or crossword puzzles.
• Schedule sedentary activities in the morning when
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
• Carbidopa/levodopa, 25 mg/100 mg, or controlledrelease (CR), 25 mg/100 mg
• Dopamine agonists, such as pramipexole or ropinirole
• Low-potency opioid analgesics, such as propoxyphene,
codeine, or tramadol
• Sedative-hypnotics such as clonazepam, temazepam,
or zolpidem*
• The non-pharmacologic approach for daily RLS is the
same as for intermittent RLS.
• Approved dopamine agonists, such as pramipexole or
ropinirole
• Gabapentin
• Other dopamine agonists
• Low or medium potency opioids, such as codeine
or tramadol
Daily RLS
Refractory RLS
• Change to a different dopamine agonist, including those
not FDA approved for treating RLS.
• Change to an anti-convulsant such as gabapentin.
• Add a second agent such as gabapentin, a sedativehypnotic, or an opioid.
• Change to a high-potency opioid such as methadone,
oxycodone and hydrocodone.
• Consider rotating treatments or a drug holiday.
• Helpful non-pharmacologic approaches should be
continued in addition to pharmacologic treatment.
* Not available in Canada
(see section on “Secondary RLS” on page 10). Resolving the
underlying disorder may then eliminate the RLS. Pharmacologic
therapy varies with the patient’s form of RLS. As of publication
(spring 2011), the only approved medications for the treatment
of RLS are the two non-ergot dopamine agonists, ropinirole
(Requip, approved in the U.S. in May 2005) and pramipexole
(Mirapex, approved in the U.S. in November 2006). Both drugs
have also been approved in Canada. They are approved only to
treat moderate-to-severe idiopathic RLS which can usually be
managed with a single dose one to three hours before bedtime
(0.25 to 4 mg of ropinirole, 0.125 to 0.75 mg of pramipexole).
Some patients require twice-daily doses of agonists when early
evening symptoms are present, typically given as an earlier dose
in the late afternoon or early evening and a second dose before
bed. The action of dopamine agonists generally commences 90
to 120 minutes after ingestion; thus, these agents must be used
preventatively and cannot be used effectively once symptoms
have started. Of course, this addresses only a subset of RLS
patients, and these two medications or other medications without
any approval for RLS are often used off-label to deal with different clinical situations or to treat patients who cannot tolerate
the dopamine agonists.
Therapy of intermittent RLS involves the use of a wide
variety of agents (Table 5) that are directed at specific problems.
Levodopa, which causes such frequent augmentation when
used regularly that it is not recommended for daily treatment,
is often helpful for intermittent RLS. Levodopa and opioids
may be useful when symptoms are unpredictable (e.g.,
an airplane trip, a long car ride, a theatrical event, etc.)
because they do not require dose titration to be effective.
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.
change to one of the non-approved agents, such as
alternate dopaminergics (although not levodopa), anticonvulsants, or opioids. Sedative-hypnotics are unlikely
to work alone in cases of refractory RLS.
Dopamine agonists need to be started with a low dose and then
titrated up to an effective dose to minimize side effects; therefore,
they are better for patients who need daily medication.
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
while adding a different drug class to permit expanded
coverage. Typical combinations have seen dopamine
agonists paired with anti-convulsants, opioids, or sedativehypnotics. Opioids may best address waking symptoms,
while anti-convulsants and sedative-hypnotics may be
particularly useful for decreasing sleep problems.
Treatment of daily RLS should begin with titrated doses of the
approved agonists, ropinirole or pramipexole. The alternate agents
should be considered as initial treatment only if there is some
contra-indication or a specific clinical situation (e.g., painful RLS
with neuropathy which may be addressed with an anti-convulsant such as gabapentin). Non-ergot agonists are highly favored
because they seem less likely to cause a rare but potentially serious
complication of fibrosis (pleuro-pulmonary fibrosis or fibrotic
cardiac valvulopathy).42,43 In fact, pergolide, an ergot agonist
that was quite successful in treating RLS, has been withdrawn
from the U.S. and Canadian markets. In the future, other
non-ergot agents or formulations may also be approve or
available off-label.
3. Considering drug holidays. In some cases, drug holidays
and rotating medications have proven useful,45 but these
are difficult regimens to manage and can cause issues when
stopping one agent leads to a flare up of RLS symptoms.
4. Using high potency opioid narcotics. Those patients
who have failed numerous medication regimens may be
managed with the use of high potency opioid narcotics.
Oxycodone, hydrocodone, and methadone have been most
used in this situation.47
As indicated earlier, refractory RLS can take various forms. There
is scant medical literature on how to address these problems. The
current recommendations, like those of the 2004 algorithm,30 are
based on the clinical opinion of experts who have had much
experience in managing the more difficult cases of RLS.
Augmentation
Augmentation currently receives the greatest attention in cases of
refractory RLS.44 Augmentation is an iatrogenic worsening of RLS
with one or more of the following features:45 an advance of the
typical time of day when symptoms begin to two or more hours
earlier than before the start of treatment; a spread of restlessness
from the legs to the arms or trunk; a shorter interval before
Several strategies may be useful in managing refractory RLS:
1. Switching to a different agent. The metabolism of
ropinirole and pramipexole is different, so either may work
when the other has not. Alternately, it may be useful to
6
used to treat refractory RLS from other causes.48 All dopaminergics
have the potential to cause augmentation; levodopa appears to be
a particularly frequent offender as augmentation may occur in up
to 80% of those treated with daily doses.49,50 Agonists seem to
cause augmentation less frequently (probably about 22-32%) but
the exact frequency remains to be determined because detection
and assessment of augmentation has not yet been rigorously
applied to suitable long-term trials. While augmentation can occur
within weeks of initiating treatment, it would appear that for
symptoms start after adopting a quiescent position (Table 6).
Augmentation requires that the patient demonstrated at least some
initial response to medication, the exclusion of other possible
causes for a worsening of symptoms, and a consistent change in
symptoms. RLS symptoms can vary from day to day and wax and
wane over longer time periods, so one day or just a couple of days
of worsened symptoms are insufficient to diagnose augmentation.
Management of augmentation follows similar approaches to those
Table 7. Pharmacologic therapy for RLS
Agent
Advantages
Disadvantages
Dopaminergic Agents
Can be used on a “one time” basis or as
circumstances may require. Useful for
persons with intermittent RLS because
dopamine receptor agonists take longer
to have an effect. May also be used to
help confirm RLS diagnosis.
Many patients on daily levodopa may
develop augmentation. Therapeutic
effect may be reduced if taken with
high-protein food. Can cause insomnia,
sleepiness, and gastrointestinal problems.
Dopamine Receptor Agonists
• pramipexole (Mirapex®) – approved
• ropinirole (Requip®) – approved
• rotigotine (Neupro®) – withdrawn
• in the U.S. due to uneven absorption
Proven to reduce subjective symptoms of
RLS, decrease periodic limb movements,
and mitigate consequences of RLS
symptoms.
Can also cause nausea and hypotension.
May cause augmentation, but less
likely to do so than levodopa.
Associated with impulse control
disorders.
Opioids
Opioids offer an effective alternative
for those whose RLS is not effectively
treated with dopaminergic agents. They
can be used on an intermittent basis or
can be used successfully for daily therapy.
Wide range of potencies.
Can cause constipation, urinary
retention, sleepiness, or cognitive
changes. Can exacerbate obstructive
sleep apnea or induce central sleep
apnea. Tolerance and dependence
possible with higher doses of stronger
agents, especially those with a
shorter half-life.
Anti-convulsants offer an effective
alternative for those whose RLS is not
effectively treated with dopaminergic
agents.
Disadvantages vary depending on agent
but include nausea, sedation, dizziness,
dermatologic conditions, hepatic
disorders, and bone marrow suppression.
Sleeping aids are most effective for
improving sleep quality for people who
experience the RLS symptoms at night.
May be used alone in patients intolerant
of dopaminergic drugs.
Can cause daytime sleepiness, gait
unsteadiness, and cognitive impairment,
particularly in the elderly.
Dopamine Precursors
• carbidopa/levodopa (Sinemet®)
• benserazide/levodopa (Madopar®)
• codeine
• hydrocodone (Vicodin®)
• methadone
• oxycodone* (Percocet®,
Roxicodone,® OxyContin®)
• tramadol (Ultram®)
Anti-convulsants
• gabapentin (Neurontin®)
• pregabalin (Lyrica®)
• carbamazepine (Tegretol®)
Sedative-hypnotics
• temazepam (Restoril®)
• clonazepam* (Klonopin®)
• zolpidem (Ambien®)*
* Not available in Canada ** Rivotril in Canada
7
agonists, it usually begins after some months or years of daily
treatment. Augmentation with agonists may also be less severe
than with levodopa, and several clinical series have suggested it can
be managed without completely stopping use of the agonist; most
experience to date has been with pramipexole.51,53 This remains to
be proven. The only non-dopaminergic reported to cause
augmentation so far is tramadol.54
We do not know how much of a problem augmentation will
become in the future for dopamine agonist therapy of RLS.
Because the dopaminergics are so effective, they are likely
to remain the mainstays of RLS treatment for many years, despite
augmentation and the development of impulse control disorders
(see page 9). No other agents have received the same degree of
clinical testing, and no drugs from other classes, except a
gabapentin pro-drug, are even likely to achieve FDA or European
approval for RLS within the next several years.
Table 8. Dosing schedule for RLS
Agent
Initial Dose
Maximum Dose
Carbidopa/Levodopa (Sinemet®)
Typical beginning doses are a half or
whole tablet of 25/100 (mg carbidopa/
mg levodopa) usually taken one hour
before symptom onset.
It is not recommended to exceed a dose of
50/200 carbidopa/levodopa in immediate
or sustained release formulations, due to
the risk of augmentation.
Pramipexole (Mirapex®)
The initial dose is typically 0.125 mg
and is titrated upward to avoid common
side effects such as nausea and orthostatic
hypotension.
The mean effective dose from multiple
studies is approximately 0.375 mg.
Patients typically habituate to side
effects in a matter of 7 to 10 days.
Maximum recommended dose is
0.75 mg.
Ropinirole (Requip®)
The initial dose is typically 0.25 mg and
is titrated upward every 2 to 3 days in
order to avoid side effects such as nausea
and orthostatic hypotension.
The average patient responds to a total
dose in the 1.0 mg/day to 2.5 mg/day
range. RLS patients typically habituate
to side effects in a matter of 7 to 10
days. Maximum recommended dose is
4 mg/day.
Opioids
• codeine 15 to 30 mg as compound
• propoxyphene HCl 65 to 130 mg
• oxycodone 5 to 10 mg
• oxycodone XR 10 mg
• tramadol 50 to 100 mg
• hydrocodone 5 to 10 mg
• methadone 5 to 10 mg
• codeine 120 mg/day
• propoxyphene HC 260 to 390 mg/day
• oxycodone 15 to 20 mg/day
• oxycodone XR 20 to 30 mg/day
• tramadol 300 to 400 mg/day
• hydrocodone 20 to 30 mg/day
• methadone 20 to 40 mg/day
Sedative-hypnotics
• clonazepam 0.25 mg**
• temazepam (Restoril®) 7.5 to 1.5 mg
• zolpidem 5 mg*
• clonazepam 2 mg/day
• temazepam (Restoril®) 30mg/day
• zolpidem 20 mg/day*
Anti-convulsants
• gabapentin 100 to 300 mg
• pregabalin 50 mg
• gabapentin 2400 mg/day
• 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 nonergot agonists, but a transdermal formulation of rotigotine has
been shown to be effective in large-scale trials.66,67 However, the
drug been at least temporarily withdrawn from the U.S. market
due to concerns about variable absorption. In Europe, there has
been extensive study of cabergoline for RLS,69-71 but it is difficult
to obtain affordable dosages in the U.S. where the drug is only
approved to treat pituitary adenomas. In Canada, it can also be
financially challenging to obtain appropriate dosages of this drug
because it is generally not covered under provincial healthcare
plans. In addition, it is an ergot-based agonist with a significant
tendency to cause fibrotic conditions, including cardiac
valvulopathies.68 Lisuride has also been tested in Europe, and it
has been suggested that there may be less fibrosis than with other
ergot compounds due to its distinctive receptor binding.
Dopaminergic Agents
Dopaminergic agents are increasingly recognized as the
mainstay of pharmacologic therapy. It should be emphasized
to patients that the doses of dopaminergic agents used to
treat RLS are much lower than those used to treat Parkinson’s
disease (PD), and that the most worrisome side effects with
these agents in Parkinson’s disease (e.g., dyskinesias) are rare
or non-existent in those treated for RLS.
The dopamine precursor levodopa is converted to dopamine in
the brain. Levodopa is formulated together with a decarboxylase
inhibitor to prevent peripheral catabolism and reduce adverse
effects due to peripheral actions (nausea, hypotension). Typical
doses are in the range of 25/100 to 50/200 (mg carbidopa/mg
levodopa) usually taken one hour before symptom onset.
Effectiveness on the first night of use at low doses supports the
feasibility of intermittent or as-needed use of levodopa, as well as
its use in a therapeutic trial for patients in whom the diagnosis of
RLS is in doubt.18 It has typical dopaminergic side effects, which
include nausea, vomiting, headache, somnolence, and dizziness. It
can be quite effective acutely in treating RLS, but because it so
readily causes augmentation, it is best used only for intermittent
treatment. A formulation with benserazide has been approved
for use for RLS in several European countries.
Opioids
Opioid medications have been known to bring relief from
RLS since first described by Willis in the 17th century.72
While opioids are frequently prescribed by RLS experts, there
have been relatively few published reports of their use. There
is one successful double-blind study of oxycodone73 and two
long-term clinical series indicating the usefulness of
opioids.47,74 The selection of any individual opioid is based
largely on physician preference; the addiction potential of
tramadol is low enough that it is prescribed as a non-controlled
substance in the United States. For patients with very severe,
nearly continuous RLS symptoms, oral methadone has been
found to be useful because of its long half-life.47
The approved non-ergot agonists ropinirole and pramipexole
are effective in RLS and can treat both the sensory and motor
symptoms (i.e., PLM).55-58 Extended release formulations of
these agonists are being developed. These agonists have the
usual dopaminergic side effects and can cause peripheral
edema. They are associated in RLS with impulse control
disorders (e.g. pathologic gambling, excessive shopping,
hypersexuality), with a frequency of 9-17% in prospective
studies. This complication develops a mean of 10 months
after treatment onset, so it it is essential to repeatedly warn
patients and inquire about symptoms at each subsequent visit.
The consequences of unrecognized impulse control disorders
can be devastating, including serious financial loss and criminal
prosecutions. However, complete resolution of the pathologic
tendencies is the general rule with discontinuation of the
causative agent.59-61 There is evidence that somnolence, including
sleep attacks, is more common in Parkinson’s disease (PD)
patients taking these agonists65 but to date this has not been a
major problem in treating RLS.62-64
No cases of augmentation have been described with opioid use
in RLS except for a small number reported for tramadol.75 Side
effects include nausea, gait unsteadiness, sedation, dizziness, and
constipation. High potency opioids may induce or exacerbate
obstructive or central sleep apnea. There are also concerns about
abuse potential, addiction, and practical problems (e.g., transfer
to non-patients when medications are not secure) arising from
the use of “controlled” drugs, and prescribers need to be sensitive
to such issues. As a result, many physicians and patients are not
comfortable using narcotic medications to treat a long-term
condition. Nevertheless, opioids often provide significant relief
for RLS when other treatments have failed and may represent
the optimum treatment for some patients.
Anti-Convulsants
The most experience in RLS has been with gabapentin, which
has shown promise in the treatment of RLS and associated sleep
disturbance.76 Gabapentin is generally well tolerated but can
cause sedation, dizziness, and unsteadiness, especially in older
individuals. It has been tested in head-to-head trials against
dopaminergics with generally comparable results,77,78 but
overall experience is less extensive. Gabapentin has less drugdrug interactions due to its renal route of excretion. It may be
particularly well suited for individuals with comorbid RLS and
The typical PD phenomena of fluctuations, dyskinesias,
hallucinations, and psychosis have at most been rare problems for
RLS patients, perhaps because of the different biology and lower
doses used. Augmentation does occur fairly frequently over the
long term, but the evidence to date indicates that, at least in
expert hands, it is often manageable without withdrawing the
9
Pregnancy
peripheral neuropathy, and it is often used as an adjunctive agent
in RLS with persistent sleep disturbance due to its mild sedative
properties. Pregabalin,79 a related compound, has been shown in
a controlled trial to be effective in managing RLS. A gabapentin
pro-drug, gabapentin enacarbil, has also been shown to be
effective, but has not been approved for use in the U.S.80
RLS also frequently occurs initially or is exacerbated during
pregnancy. New-onset RLS generally appears in the last
trimester and clears with delivery. The cause of the increased
incidence of RLS during pregnancy remains uncertain. While
having been pregnant may be a risk factor for later RLS,87 we
do not yet know whether those who develop RLS during
pregnancy are also at increased risk for later RLS. Treatment
of RLS in pregnant women is hampered by the limited
information about which drugs are safe during pregnancy.
Pregnant women are often iron deficient and may benefit
from iron supplementation. For more information, please see
the separate booklet, Pregnancy and RLS: Vital considerations
in treating a pregnant patient who has restless legs syndrome
(RLS), which can be downloaded at www.rls.org/publications.
Sedative-Hypnotics
Benzodiazepines (particularly clonazepam**) have been
extensively used for evening and nocturnal RLS due to
their ability to induce and maintain sleep; however, their
therapeutic effects in this condition have not been extensively
studied. The recent development of dopaminergic agents
with improved symptom relief has relegated benzodiazepines
to second-line status or when insomnia persists after elimination
of RLS symptoms. Clonazepam** was found very effective
and well tolerated in a long-term study of sleep-disrupted
patients.81 However, this longer acting agent has a higher
frequency of daytime somnolence and cognitive disturbance
(5-15%) than sedative-hypnotic drugs with shorter durations
of action (but even less evidentiary support), such as
temazepam and zolpidem.* Another factor to consider is that
clonazepam** is available as a generic with quite modest cost
to the patient. As with opioids, careful screening for past
drug or alcohol misuse, abuse, or dependency is important,
and close monitoring is necessary.
Iron Deficiency
Serum levels of ferritin, the primary storage unit for iron, have been
found to correlate inversely with RLS severity.35,36 The lower the
iron level and the more acute the onset of symptoms, the more
likely it is that improvement can be expected in RLS symptoms
with iron supplements. The value of raising ferritin levels much
above 50 µg/L remains unclear. Iron treatment can be instituted
with ferrous sulfate, 325 mg three times a day with 500 mg of
vitamin C (to acidify the stomach and promote absorption) or
comparable doses of elemental iron. Intravenous iron improved
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
different formulations and establish RLS benefit, this treatment
should be restricted to patients with a diagnosis of definite iron
insufficiency who have malabsorption states preventing oral iron
absorption or complete intolerance to oral iron preparations. With
the institution of oral iron supplementation, serum ferritin levels
and percent transferrin saturation (%sat) should be checked at
intervals not longer than every three months. Supplemental iron
may be discontinued once the patient’s serum ferritin level reaches
50 µg/L and should not be continued if %sat >50% given the risks
of hemochromatosis.91 Low ferritin or anemia may also be a sign of
bleeding and may indicate the need for a workup. RLS has been
the presenting symptom of colon cancer.92
Secondary RLS
End-Stage Renal Disease (ESRD)
It has been recognized for over 40 years that, in comparison
to the general population, RLS is more common in individuals
with ESRD both before and after the institution of dialysis.
Recent prevalence studies indicate that the rates of RLS
among this patient group range from 6-83%, varying with
racial groups and with modes of management. Both RLS and
a PLM index greater than 20 are significant independent
predictors of mortality in this population.82,83 Quality of life
is also adversely affected.84,85
Children & RLS
The causes of the high prevalence of RLS in ESRD remain
to be fully described. Anemia has been linked to RLS, and
normalization of hematocrit with recombinant erythropoietin
has resulted in a significant reduction in PLM.83 Most general
RLS medications work in uremia, though doses and their
timing may need to be adjusted to compensate for kidney
failure. Transplantation, but not dialysis, improves and
sometimes cures RLS in uremia.
Recent literature reveals that RLS occurs more frequently in
children than previously recognized.4 Young children present
a diagnostic challenge since many symptoms of RLS are
subjective and difficult to explain, even for adults. A
workshop at the National Institutes of Health (NIH) in May
2002 resulted in specific consensus criteria for the diagnosis
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
*Not available in Canda **Rivotril in Canada
10
Table 9. RLS diagnosis in children
deficit/hyperactivity disorder (ADHD)) and oppositional
behaviors (oppositional defiant disorder), may be more
common in these children.97,98 Further research is needed to
understand the association of these disorders with RLS and
PLMS; a possible biologic basis may lie in iron deficiency in
children which has been associated both with RLS and ADHD.99-101
Definite RLS
1. The child meets all four essential adult criteria
for RLS, and
2. The child relates a description in his or her own words
that is consistent with leg discomfort. (The child may
use terms such as oowies, tickle, spiders, boo-boos,
want to run, and a lot of energy in my legs to describe
symptoms. Age-appropriate descriptors are encouraged.)
Treatment
There are limited investigations of treatment for RLS in the
pediatric population. Most “evidence” is gleaned from a few
case reports and two case series of children with RLS and/or
periodic limb movement disorder (PLMD). The case reports
have indicated individual responses to strict limit-setting to
promote a good sleep schedule, restriction of caffeine, iron
supplementation, and medications such as clonazepam,
carbidopa/levodopa, pergolide, pramipexole, ropinirole, and
clonidine.102,103 In children with iron deficiency (as determined
by measurement of serum ferritin levels), therapy to correct
the iron deficit can successfully relieve RLS symptoms. As to
safety in children, medications such as benzodiazepines, anticonvulsants, alpha-adrenergic agents, and opioids have been
used extensively in children with disorders other than RLS, as
has chronic use of levodopa for dopa-responsive dystonia.104
In a small open-label trial of dopaminergic medication used
in six children with RLS and ADHD, an improvement was
demonstrated in RLS symptoms and sleep, as well as in
scores of attention and impulsivity.102 In association with any
medical therapy for RLS, it is implicit that interventions for
behavioral-, sleep schedule-, and sleep hygiene-related problems
occur before or in coordination with the medical therapy.
OR
1. The child meets all four essential adult criteria for
RLS, and
2. Two of three supportive criteria are present:
a. Sleep disturbance for age.
b. A biologic parent or sibling has definite RLS.
c. The child has a polysomno-graphically
documented periodic limb movement index
of 5 or more per hour of sleep.
were developed to promote research in this area. For more
information, please see the RLS Foundation’s Children and
RLS: Restless Legs Syndrome and Periodic Leg Movement
Disorder in Children and Adolescents: A Guide for Healthcare
Providers available for download at www.rls.org/publications.
Diagnosis in Children
References
As in adults, the symptoms of RLS in children may include
leg discomfort, sleep onset problems, and sleep maintenance
problems. In some children, the RLS discomfort may be
misdiagnosed as “growing pains”.93,94 Diagnosis in children
requires both an understanding of the adult features of RLS
and additional potential diagnostic elements (Table 9).
Approximately 40% of adults with RLS report the onset of
RLS prior to age 21.29 However, the identification of RLS
in pediatric practices is often poor due to lack of knowledge
about the disorder. Features seen in children that aid
diagnosis (such as the presence of periodic limb movements,
sleep disturbance, and family history) can be seen without
actual symptoms of RLS. These may be precursors of
development of the full syndrome.95 PLM in children may
be hard to diagnose adequately due to their higher night-tonight variability. Therefore, they may require multi-night
recordings for adequate diagnosis; this can be most easily
accomplished with accelerometry.100
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Restless legs syndrome can be a serious disorder. Persons suspecting
that they may have RLS should contact a qualified healthcare
provider. Literature concerning RLS that is distributed by the
Restless Legs Syndrome Foundation, Inc., is offered for information
purposes only and should not be considered a substitute for the
advice of a healthcare provider.
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13
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