INTRODUCTION
Restless legs syndrome (RLS) refers to
symptoms of spontaneous, continuous leg movements
associated with unpleasant paresthesias. These
sensations occur only at rest and are relieved by
movement. Sleep disturbance and a frequent
association with involuntary, jerking movements of
the legs during sleep, known as periodic leg
movements of sleep (PLMS), are common. Nocturnal leg
cramps are a separate disorder.
EPIDEMIOLOGY Mild symptoms of RLS occur in 5
to 15 percent of the population; prevalence figures
vary widely depending upon the population surveyed
and severity of symptoms required for inclusion.
In a population study of RLS that used standard
diagnostic criteria, 15,391 subjects (18-years-old)
from the United States and five European countries
(France, Germany, Italy, Spain, and the United
Kingdom) completed questionnaires and the following
observations were made: RLS symptoms of any
frequency were reported by 7.2 percent. RLS symptoms
occurred at least twice a week and were reported as
moderately or severely distressing by 2.7 percent.
The prevalence of RLS was approximately twice as
high for women compared with men. The prevalence of
RLS increased with age up to age 79, and then
declined.
A previous survey also found that the prevalence of
restless legs (with symptoms experienced on five or
more nights per month) increased with age, from 3
percent of participants ages 18 to 29, compared with
10 percent of those ages 30 to 79 and 19 percent of
those ages 80 or older. Increasing parity may be
associated with an increased risk of RLS.
RLS also occurs in children. In a questionnaire
study of patients with RLS, 25 percent experienced
their first symptoms between ages 11 and 20.
Misdiagnoses such as "growing pains" and attention
deficit hyperactivity disorder were common, and
medical attention was often not sought until after
age 40 when symptoms frequently begin to progress.
In a retrospective study, 32 of 538 children and
adolescent subjects (5.9 percent) presenting to a
sleep disorders clinic had restless legs syndrome.
Low serum ferritin (<50 g/L) was found in 20 of 24
subjects (83 percent) who had ferritin levels. A
family history of RLS was present in 23 of 32 (72
percent) subjects, and mothers were nearly threefold
more likely to be affected than fathers.
PATHOGENESIS In most cases RLS is a primary
idiopathic disorder, but it also can be associated
with a variety of underlying medical disorders.
Primary RLS The cause of primary,
idiopathic RLS is unknown. A family history
consistent with dominant inheritance is present in
more than 40 percent of patients with idiopathic
RLS. This observation in combination with several
large kindreds with RLS that have been reported
suggest a genetic basis for the disorder. A genetic
component is further supported by a twin study in
which 10 of 12 monozygotic twin pairs were
concordant for RLS, although there was considerable
variance in age of onset and symptom severity.
Genetic linkage studies have mapped at least four
susceptibility loci for RLS: chromosome 12q13-23,
chromosome 14q13-21, chromosome 9p24-22, and
chromosome 20p13.
There is a high incidence of RLS in spinocerebellar
ataxia type 3 (Machado-Joseph disease), which is
unrelated to the incidence of peripheral neuropathy
in that disorder.
Several neurophysiologic changes have been
identified in patients with RLS, including reduced
motor cortex inhibition, spinal flexor reflex
hyperactivity, and brainstem reflex abnormalities,
but these are nonspecific findings, the significance
of which is currently undetermined.
It has been assumed that RLS is a peripheral
disorder, but studies of brain dopamine metabolism
raise the possibility of a central nervous system
cause. One hypothesis holds that RLS arises from
dysfunction of hypothalamic dopaminergic cells that
are the source of spinal cord dopamine. Data from
functional imaging with single photon emission
computed tomography (SPECT) and positron emission
tomography (PET) are conflicting, having
demonstrated reduced, increased, or unchanged basal
ganglia dopamine receptor binding and 18F-Dopa
uptake in patients with RLS compared with control
subjects. This is of particular interest since there
is probably an increased incidence of RLS in
Parkinson's disease. Brain iron metabolism may also
play a role.
Hypocretins are hypothalamic
neuropeptide transmitters that participate in the
normal control of the sleep wake cycle and are
depleted in the pathophysiology of narcolepsy.
Hypocretins increase arousal and interact with the
dopamine system. A small clinical study also found
that increases in hypocretin levels in the
cerebrospinal fluid were associated with an
increased incidence of restless legs syndrome,
particularly early onset disease.
Secondary RLS RLS can occur secondary to a
number of disorders including iron deficiency,
uremia, diabetes mellitus, rheumatic disease, and
venous insufficiency, among others.
Iron deficiency Iron deficiency has been
considered a possible cause of RLS since the
original publications on this disorder.
Subsequently, the relationship between iron status
and RLS has been examined in several studies: In a
report of 18 elderly patients with RLS and 18
matched controls, the serum ferritin concentration
was significantly lower in patients with RLS (33
versus 59 mcg/L) and was inversely correlated with
the severity of symptoms. Although the hemoglobin
concentration in patients and controls was similar,
treatment with ferrous sulfate for two months
reduced RLS symptoms in 14 of 15 patients. In a
second study, patients with RLS had a lower spinal
fluid ferritin concentration than age-matched
controls (1.11 versus 3.50 ng/mL) and a higher
spinal fluid transferrin concentration (26.4 versus
6.71 ng/mL). However, there was no difference in
serum ferritin and transferrin between the two
groups. A study that performed MRI estimates of
brain iron concentration in a small number of
patients with RLS found significantly reduced iron
in the substantia nigra. Neuropathological studies
found altered iron management protein levels that
were consistent with iron insufficiency in
substantia nigra neuromelanin cells from patients
with RLS. Quantitative analyses showed decreased
levels of ferritin, divalent metal transporter 1
(DMT1), ferroportin, transferrin receptor, and iron
regulatory protein 1 (IRP1) compared with controls.
While these findings are not conclusive, they
warrant the measurement of serum ferritin levels in
patients with RLS and a trial of oral iron therapy
when ferritin levels are low. Oral iron therapy may
also be considered when ferritin levels are within
normal range, as some patients without iron
deficiency may still respond.
End-stage renal disease RLS is common among
dialysis patients, with a reported incidence of 6 to
60 percent. Anemia may play a role in these
circumstances, since low-dose erythropoietin therapy
significantly reduced RLS in one report. In
addition, iron therapy among dialysis patients with
functional, but not absolute, iron deficiency was
beneficial in another study. A third study,
however, found that a low serum parathyroid hormone
concentration, but not serum hemoglobin, was
associated with the presence of RLS in 136 dialysis
patients.
Diabetes mellitus RLS can be a prominent
feature of diabetic neuropathy. RLS and other
sensory symptoms of neuropathy often improve
following successful pancreatic-kidney
transplantation.
Parkinson's Disease (PD) Both RLS and PD
appear to involve disturbances in the dopaminergic
neurotransmitter system, suggesting a common
mechanism. However, few studies have examined the
relationship between these two disorders, and
progress is hampered by a lack of understanding
regarding the pathophysiology of RLS. In contrast to
PD, preliminary neuropathologic evidence suggests
that the pathogenesis of RLS does not involve
neuronal degeneration of nigrostriatal pathways.
Estimates of the prevalence of RLS among patients
with Parkinson's disease vary widely from 0 to 20.8
percent; some but not all studies have found that
the prevalence of RLS is higher in patients with PD
than in the general population. Akathisia is also
common in PD, with prevalence rates ranging from 26
to 45 percent and the potential for overlap with
RLS. One series found that patients with both PD and
RLS were older at RLS onset, were less likely to
have a family history of RLS, and had lower serum
ferritin levels compared with patients with
idiopathic RLS. When both disorders were present, PD
preceded RLS in 68 percent of patients.
Pregnancy Pregnancy appears to be a risk
factor for the occurrence or worsening of RLS. In a
study of 626 pregnant women admitted to a single
center, the diagnosis of RLS was determined by the
four International RLS Study group criteria; the
prevalence of RLS in this group of women was 10
percent before pregnancy and increased to 27 percent
during pregnancy. The highest rates were seen in the
third trimester and dropped quickly after delivery.
Older studies have reported lower rates of RLS
during pregnancy, but none of them had used or
strictly applied the four standard diagnostic
criteria. The cause of the increased frequency of
RLS during pregnancy is unclear, but possible causes
include iron deficiency, folate deficiency, and
hormonal changes.
Rheumatic disease The relationship between
RLS and rheumatic disease is unclear. In one study,
RLS was present in 25 percent of patients with
rheumatoid arthritis compared with 4 percent of
controls with osteoarthritis or seronegative
arthropathy and was associated with greater disease
activity and severity. A higher than expected
prevalence of RLS has also been reported in patients
with Sjφgren's syndrome, and in a study of 135
patients with fibromyalgia, 42 had RLS. In contrast,
another study carried out in a neurology specialty
clinic found no evidence of clinical rheumatologic
disease among 68 patients with RLS, and only four
patients had positive serologies for rheumatic
diseases.
Venous insufficiency Varicose veins have been
associated with RLS and treatment of varicose veins
and chronic venous insufficiency may be helpful in
some patients. As an example, one study found that
312 of 1397 patients seeking treatment for varicose
veins had symptoms of RLS on a screening
questionnaire and interview. Sclerotherapy was
performed in 113 of the patients with RLS; 98
percent reported initial relief of RLS. Symptom
relief was maintained in 72 percent at two years of
follow-up.
Treatment of chronic venous insufficiency with
hydroxyethylrutoside also appears to be beneficial
in patients with RLS but not as striking or dramatic
as sclerotherapy. A meta-analysis of 15 trials that
included a total of 1973 patients found that RLS
improved in 36 percent of those treated with an
average dose of 1000 mg/day for a minimum of four
weeks compared with 26 percent of placebo controls.
Other miscellaneous conditions Other
disorders that are reported to be associated with
RLS include other peripheral neuropathies, vitamin
deficiencies, lumbosacral radiculopathy, spinal
stenosis, excess caffeine intake, administration of
mianserin, hypoglycemia, and hypothyroidism.
CLINICAL MANIFESTATIONS Although the
subjective symptoms of RLS are often difficult to
describe, the clinical features are highly
stereotyped. The hallmark of RLS is a marked
discomfort in the legs that occurs only at rest and
is immediately relieved by movement. The abnormal
feelings are typically deep seated and localized
below the knees. Distribution is usually bilateral,
but some asymmetry may occur and the arms can be
affected in more severe cases.
Terms that patients use to describe the symptoms
include crawling, creeping, pulling, itching,
drawing, or stretching, all localized to deep
structures rather than the skin. Pain and tingling
paresthesia of the type that occurs in painful
peripheral neuropathy is usually absent, and there
is no sensitivity to touching of the skin.
Symptoms typically worsen towards the end of the day
and are maximal at night, when they appear within 15
to 30 minutes of reclining in bed. In severe cases
symptoms may occur earlier in the day while the
patient is seated, thereby interfering with
attending meetings, sitting in a movie theater, and
similar activities. In milder cases patients will
fidget, move in bed, and kick or massage their legs
for relief. Patients with more severe symptoms feel
forced to get out of bed and pace the floor to
relieve symptoms.
Periodic leg movements of sleep PLMS are sudden
jerking leg movements that commonly accompany RLS.
The patient is usually unaware of these movements.
The prevalence of PLMS increases with age, and PLMS
are identified in the vast majority of patients with
RLS during sleep laboratory evaluations.
Treatment is not necessary if PLMS occur without
sleep complaints. However, in some patients, the
periodic limb movements may cause partial or total
arousal from sleep and provide an additional cause
of insomnia and excessive daytime drowsiness.
Periodic limb movement disorder (PLMD) of sleep is
the term used to characterize the association of
PLMS and hypersomnolence.
Although data are limited, treatment of symptomatic
PLMD is approached using the same drugs and regimens
as used to treat RLS, particularly when PLMD is
accompanied by RLS. Benzodiazepines and pramipexole
are often used to treat PLMD in the absence of RLS.
DIAGNOSIS The diagnosis of RLS is often
delayed or missed, especially when the symptoms are
relatively mild or non-specific. The diagnosis of
primary RLS rests on typical symptoms in the
presence of a normal neurologic examination.
Patients with secondary forms of RLS due to
peripheral neuropathy may have related sensory and
reflex abnormalities. The International Restless
Legs Study Group proposed the following four
features as minimal criteria for the diagnosis of
RLS: Desire to move the extremities, often
associated with paresthesias or dysesthesias. Motor
restlessness. Worsening of symptoms at rest with at
least partial and temporary relief during activity.
Worsening of symptoms in the evening or at night
Polysomnography in a sleep laboratory is not
necessary for the diagnosis, but it may be helpful,
especially when RLS is resistant to treatment. In
such cases coexisting PLMS may be identified in the
majority.
The differential diagnosis begins with separating
primary from secondary RLS. Iron deficiency and
renal failure are particularly important to exclude;
a normal hemoglobin does not rule out iron
deficiency if the serum ferritin is low. Peripheral
neuropathy, lumbosacral radiculopathy, and ordinary
leg cramps, all of which are typically more painful
conditions, should also be considered.
RLS should be differentiated from akathisia, a
common side effect of the phenothiazine
antipsychotic drugs and selective serotonin reuptake
inhibitor (SSRI) antidepressants. Akathisia (from
the Greek "not to sit") is a more constant and
generalized feeling of motor restlessness
unassociated with subjective discomfort localizing
to the legs. In contrast to akathisia, RLS has a
circadian rhythm (worse at night when the patient is
sitting or in bed) and is commonly accompanied by
paresthesias and myoclonic jerks during the waking
state. The syndrome of "painful legs and moving
toes" is a rare disorder of unknown cause
characterized by more prominent involuntary toe
movements and leg pain.
TREATMENT A number of treatments for RLS have
been studied in primarily small, randomized,
controlled trials. Placebo controlled studies are
particularly important since RLS is normally
characterized by fluctuations and remissions.
Early reports described the benefit of vasodilators,
iron, and vitamins, but currently these agents are
rarely used except for iron in demonstrated iron
deficiency anemia. Stretching exercises for the
posterior leg muscles may be helpful before retiring
for patients with persistent symptoms.
Pharmacotherapy for idiopathic RLS with
benzodiazepines, dopaminergic drugs, or, in
resistant cases, opioids has been successful in many
patients. Dopaminergic drugs such as levodopa
(L-dopa) and dopamine agonists appear to be more
effective than benzodiazepines in patients with RLS,
although there are no direct comparison studies.
Expert panel recommendations An algorithm
for the management of RLS devised by an expert panel
(the Medical Advisory Board of the Restless Legs
Syndrome Foundation) was published in July 2004 and
highlights three particular types of RLS
(intermittent, daily, and refractory).
Recommendations for these three types are excerpted
here.
Intermittent RLS Intermittent RLS is
defined as RLS that is troublesome enough when
present to require treatment but that is not
sufficiently frequent to require regular daily
medication use. Treatment options include:
Nonpharmacologic therapy. Levodopa. Dopamine
agonists. Low potency opioids or opioid agonists.
Benzodiazepines or benzodiazepine agonists.
Daily RLS Daily RLS is defined as RLS that
is frequent and troublesome enough to require daily
treatment. Treatment options include:
Nonpharmacologic therapy. Dopamine agonists
Gabapentin. Low potency opioids or opioid agonists
Refractory RLS Refractory RLS is defined as
daily RLS treated with a dopamine agonist but with a
poor response. The response is considered poor if
there is an inadequate initial response despite
adequate doses of medication or if the response
becomes inadequate with time despite increasing
doses. Augmentation (the onset of symptoms earlier
in the day or extension of symptoms to arms or
trunk) that is not controllable with additional
earlier doses of the drug also qualifies RLS as
refractory, as does intolerable adverse effects.
Referral to a specialist for RLS management should
be considered for these patients. Four different
pharmacologic treatment approaches are recommended:
Change to gabapentin. Change to a different dopamine
agonist. Add a second agent such as gabapentin, a
benzodiazepine, or an opioid. Change to a high
potency opioid or tramadol
Levodopa The efficacy of L-dopa has been
demonstrated in small randomized trials: In one
double-blind, crossover study lasting four weeks, an
evening dose of L-dopa 200 mg with benserazide (a
peripheral dopa decarboxylase inhibitor used in
Europe and equivalent to carbidopa used in the
United States) significantly reduced the frequency
of awakenings and duration of waking periods in 13
patients with RLS compared with placebo. In a second
double-blind trial in which 20 patients with RLS
were given L-dopa, 50 to 200 mg daily with
benserazide or lactose on alternate days for an
unspecified period of time, 17 patients reported
complete relief with L-dopa. L-dopa was also
effective in a double-blind study of uremic RLS.
Tachyphylaxis (a decreasing response with continual
treatment) to L-dopa has been reported, but in one
long-term study lasting two years, 26 of 30 patients
initially responding to L-dopa maintained a good
response.
Three different problems may occur with patients on
L-dopa therapy: Augmentation is a worsening of RLS
symptoms earlier in the day after an evening dose of
medication, including earlier onset of symptoms,
increased intensity of symptoms, or spread of
symptoms to the arms. It occurs in up to 70 percent
of patients taking daily L-dopa. Rebound is the
recurrence of RLS early in the morning. It occurs in
20 to 35 percent of patients taking L-dopa.
Recurrence of symptoms in the second half of the
night may occur.
An expert advisory panel on RLS recommends L-dopa
only for intermittent RLS. The risk of augmentation
may be decreased with intermittent use of
dopaminergic drugs, although this has not been well
studied. The expert panel recommends discontinuation
of the drug if augmentation occurs. Controlled
release L-dopa (CR) combined with standard L-dopa
may help sleep quality during the second half of the
night for patients who experience recurrence.
For best absorption, L-dopa should not be taken with
high protein foods. Suggested agents include:
Carbidopa/levodopa 25 mg/100 mg, one-half or one
tablet, can be used for intermittent RLS that occurs
during the evening, at bedtime, or on waking during
the night. Additionally, this medication may be
helpful for RLS associated with specific triggers
including lengthy travel by auto or airline, or
spectator events with prolonged sitting. Controlled
release (CR) carbidopa/levodopa, 25 mg/100 mg before
bed may be helpful for RLS that awakens the patient
during the night.
Dopamine agonists Dopamine agonists belong
to a class of drugs that directly stimulate dopamine
receptors and have a longer half-life (four to six
hours) than levodopa (90 minutes). They are
generally superior to levodopa for the treatment of
daily RLS.
Pramipexole and ropinirole The non-ergot dopamine
agonists, pramipexole and ropinirole, are less
likely to cause side effects compared with other
dopamine agonists. These agents are considered to be
the drugs of choice in most patients with daily RLS.
They may also be helpful in patients with
intermittent RLS. Both ropinirole and pramipexole
are approved by the the United States Food and Drug
Administration (FDA) for the treatment of RLS. The
benefit of ropinirole for RLS was demonstrated in
three similar randomized controlled trials. As an
example, one of these trials enrolled 284 patients
with moderate to severe RLS; improvement on the
primary outcome measure of symptoms as assessed by
the International Restless Legs Scale (IRLS) was
significantly greater for ropinirole treatment
(average dose 1.13 mg/day) than for placebo. The
benefit of pramipexole was demonstrated in a 12-week
double-blind trial that assigned 344 patients with
moderate or severe RLS to one of three pramipexole
regimens (0.25, 0.50, and 0.75 mg/daily) or to
placebo. The initial pramipexole dose was 0.125
mg/daily for the first week, and the dose was
titrated up to the assigned dose over the first
three weeks of the trial. All three doses of
pramipexole were superior to placebo on the two
primary outcome measures (patient-rated symptom
severity improvement measured by the IRLS, and
clinician-rated improvement). Pramipexole was well
tolerated; nausea and somnolence were the most
frequent side effects associated with its use.
An earlier, small (n = 10) double-blind, crossover
study lasting two months found that pramipexole
markedly reduced RLS symptoms for 24 hours following
a single evening dose and also reduced the frequency
of periodic leg movements of sleep (PLMS) to normal
levels. The initial pramipexole dose was 0.375
mg/day, and the dose was increased to 0.75 mg after
one week and 1.5 mg/day after the second week. Seven
of the 10 patients who participated in this study
were followed for an additional mean period of 7.8
months with no decrease in benefit, increase in dose
requirement, or shift of symptoms to daytime. The
optimal pramipexole dosage was 0.25 mg for one
patient, 0.5 mg for five patients and 0.75 mg for
one patient.
Adverse effects with pramipexole and ropinirole have
been mild and transient and limited to nausea,
lightheadedness, and fatigue; these usually resolve
within 10 to 14 days. Less frequent side effects
include nasal stuffiness, constipation, insomnia,
and leg edema; these are reversible if the
medication is stopped. Sudden, unexpected sleep
attacks, as described in patients with Parkinson's
disease (PD) on higher doses of pramipexole, do not
appear to occur in patients on low-dose pramipexole
(mean of 0.37 mg/day) for RLS.
The onset of action for dopamine agonists is
typically 90 to 120 minutes after intake. Therefore,
these medications should be started two hours before
RLS symptoms start. The recommended starting doses
are: Pramipexole 0.125 mg once daily. The dose may
be increased by 0.125 mg every two to three days
until relief is obtained. In a clinical trial, all
three doses of pramipexole (0.25, 0.50, and 0.75
mg/daily) were equally effective, and some patients
responded to the initial dose of 0.125 mg daily.
However, side effects were more common with the 0.50
mg and 0.75 mg daily. Therefore, it is expected that
0.25 mg daily has the best therapeutic margin. Most
patients require 0.5 mg or less, but doses up to 2
mg may be needed. Ropinirole 0.25 mg once daily. The
dose may be increased by 0.25 mg every two to three
days until relief is obtained. Most patients require
2 mg or less, but doses up to 4 mg or higher may be
needed.
Augmentation is less common with these drugs than
with levodopa, but it has been reported in up to
one-third of patients taking pramipexole for two
years. The risk of augmentation with ropinirole is
unknown. In one study, augmentation was
significantly more common in patients with a family
history of restless legs syndrome and in those who
had no evidence of neuropathy on electromyography or
nerve conduction studies.
Unlike levodopa, additional doses of a dopamine
agonist earlier in the day can often reduce the risk
and intensity of augmentation. The development of
augmentation with one dopamine agonist does not
necessarily predict augmentation with a different
agonist. In addition, ropinirole and pramipexole can
be substituted for one another. However, therapy
should be changed to a different class of
medications if augmentation develops with a second
dopamine agonist.
Other dopamine agonists Other dopamine
agonists may also be effective in RLS but are used
infrequently. Cabergoline
(0.5 to 4 mg as an evening dose) is a dopamine
agonist with a long half-life (65 hours) that may
benefit patients who experience rebound symptoms
with shorter half-life medications.
In a five-week randomized clinical trial of 85
patients with RLS, cabergoline at doses of 0.5, 1.0,
and 2.0 mg/day (taken at least three hours before
bedtime) was effective compared with placebo in
treating RLS symptoms and sleep disturbance. In an
open-label, one-year extension, a mean daily dose of
cabergoline 2.2 mg/day was required to maintain
improvement of RLS symptoms. A later five-week
randomized controlled trial of 40 patients with
moderate to severe RLS found that cabergoline 2 mg
once daily in the evening was significantly more
effective than placebo by polysomnography for
reducing PLMS-related arousal.
Side effects in the first trial including nausea,
constipation, headache, dizziness, fatigue, and
drowsiness caused treatment discontinuation in 11
patients (13 percent). Augmentation (the onset of
symptoms earlier in the day or extension of symptoms
to arms or trunk) was observed in six treated
patients (9 percent) in the long-term phase. In a
study of patients with Parkinson's disease, high
cumulative dose and long-term treatment with
cabergoline was associated with an increased risk of
cardiac valvulopathy.
Cabergoline is approved by the FDA only for the
treatment of hyperprolactinemic disorders, and its
use for RLS is off-label. Several controlled
clinical trials have demonstrated that pergolide is
effective for relieving symptoms of RLS. However,
pergolide was associated with restrictive cardiac
valve disease in 33 percent of patients when used in
high doses to treat PD, and this risk would likely
preclude its use in RLS. In addition, pergolide is
associated with an increased risk of pleuropulmonary
fibrosis.
Benzodiazepines Benzodiazepines are useful
in mild cases of RLS, particularly in younger
patients. Diazepam has
been used in RLS for many years, although there have
been no controlled trials. In a small randomized,
double-blind, crossover trial, treatment with
clonazepam, 1.0 mg daily, was superior to placebo in
six patients with RLS. In an open trial, 14 of 15
patients with RLS due to uremia responded to
clonazepam, 1 to 2 mg daily.
An RLS expert panel algorithm recommends
benzodiazepines or benzodiazepine agonists for
intermittent RLS, especially if the patient has
another cause of poor sleep in addition to RLS.
Short-acting agents can be helpful for sleep onset
insomnia caused by RLS; these agents include:
Triazolam 0.125 to 0.5 mg Zolpidem 5 to 10 mg
Zaleplon 5 to 10 mg. For RLS that awakens the
patient later in the night, the expert panel
recommends intermediate acting agents such as
temazepam 15 to 30 mg.
Although most trials have been performed with
clonazepam, its long duration of action may result
in more adverse effects, such as nocturnal
unsteadiness and drowsiness or cognitive impairment
in the morning. However, at least one study has
shown a low rate of adverse effects from clonazepam
in elderly patients. Long-term maintenance treatment
with benzodiazepines is limited by tolerance in many
patients, but abuse appears to be low in this
disorder.
Opioids A variety of opioids, including
codeine, methadone, and propoxyphene, have been
reported to be helpful for RLS in uncontrolled
trials. In a double-blind, four week crossover study
of 11 patients, oxycodone at a mean dose 15.9
mg/day, was superior to placebo with regard to
number of sleep arousals, PLMS frequency, and sleep
efficiency. One long-term retrospective study of 113
patients treated with opioids has shown persistent
benefit, but a small number of patients developed
sleep apnea. Similar to benzodiazepines, opioid
abuse potential is low in patients with RLS.
Nevertheless, we typically restrict use to patients
with more severe symptoms who fail to respond to
benzodiazepines or dopaminergic drugs.
The expert RLS panel recommends more liberal use of
low potency opioids or opioid agonists for
intermittent RLS and as an alternative for daily
RLS. These drugs are usually taken before bed and
include: Propoxyphene napsylate 100 to 200 mg.
Propoxyphene hydrochloride 65 to 130 mg. Codeine 30
to 60 mg, usually in combination preparations with
acetaminophen. Tramadol 50 to 100 mg before bed or
during the night.
For patients with refractory RLS, the same panel
recommends change to a high potency opioid or
tramadol as one of four different management
approaches. High potency opioids may be effective in
the management of RLS, and escalation of doses and
dependence are uncommon in the absence of a history
of substance abuse. High potency opioids may be used
one to three times a day depending on timing of
symptoms; agents include: Oxycodone 5 to 15 mg.
Hydrocodone 5 to 15 mg. Methadone 5 to 10 mg.
Tramadol 50 to 100 mg
Gabapentin Gabapentin is an alternative
choice for patients with daily RLS. Gabapentin, mean
dose 733 mg/day, was effective in a four-week
open-label study of nine patients with idiopathic
RLS, and at a much higher mean dose (1,855 mg) in a
randomized, placebo-controlled trial of 22 patients.
Among dialysis patients, gabapentin (200 to 300 mg
three times weekly after hemodialysis) was effective
in a 12-week, double-blind crossover study.
Although the trial data above suggest that mean
doses of 1800 mg a day are needed, many patients
appear to benefit from a lower dose. The expert
panel suggests beginning treatment with 100 to 300
mg per dose because of the tendency of the drug to
cause somnolence and gait unsteadiness.
Gabapentin may be particularly useful in patients
whose symptoms are less intense and in patients in
whom RLS is perceived as painful. It may also be
useful when RLS occurs in the setting of a painful
peripheral neuropathy or an unrelated chronic pain
syndrome. Gabapentin may also be considered in the
treatment of RLS in association with
neurodegenerative disorders, such as PD or dementia.
Other drugs Other drugs that may be useful
in RLS but have been reported in only a small number
of mainly open studies include
carbamazepine (mean dose 236 mg/day),
clonidine (0.05
mg/day), propranolol
(40 to 120 mg/day), and
amantadine (up to 300 mg/day).
Nonpharmacologic therapy Nonpharmacologic
therapy is recommended by the expert panel for
patients with intermittent or daily RLS. The therapy
involves the following components: Iron replacement
therapy. Mental alerting activities. Avoidance of
aggravating factors.
Iron replacement Administer iron
replacement if the serum ferritin level is lower
than 45 to 50 mcg/mL. The suggested regimen is
ferrous sulfate (325 mg three times a day) in
combination with vitamin C (100 to 200 mg) with each
dose of ferrous sulfate to enhance absorption.
Ferritin levels should be checked after three to
four months of therapy and then every three to six
months until the serum ferritin level is greater
than 50 mcg/mL and iron saturation is greater than
20 percent.
Mental alerting activities Mental alerting
activities, such as video games or crossword
puzzles, may reduce symptoms at times of boredom.
Aggravating drugs Caffeine, nicotine, and
alcohol may aggravate RLS symptoms. A trial of
abstinence is reasonable in many patients.
Antidepressants, neuroleptic agents,
dopamine-blocking antiemetics such as
metoclopramide, or sedating antihistamines
(including those found in nonprescription
medications) may contribute to RLS symptoms.
However, discontinuation may not be possible without
causing patient harm. If antidepressants are
necessary, the symptoms of secondary RLS can usually
be treated in the same way as primary RLS. Bupropion
is an alternative antidepressant that may be less
likely to induce or worsen RLS.
RECOMMENDATIONS The following sequence of
pharmacologic therapy in patients with RLS is
recommended: Begin with pramipexole (0.125 mg) or
ropinirole (1.0 mg) approximately one hour before
the usual time of symptom onset; the dose is
titrated upward according to response. These drugs
are effective and well tolerated by most patients.
Pramipexole doses above 0.75 mg/day and ropinirole
doses above 4 mg/day are of unproven benefit. An
alternative is levodopa/carbidopa, 25/100 mg given
before symptom onset in patients unable to tolerate
a dopamine agonist. In some cases a controlled
release formulation of levodopa may be necessary to
get the patient through the night or to avoid
rebound daytime symptoms. Clonazepam, 0.5 mg before
sleep can be used alone or as adjunctive treatment.
Gabapentin may be a good additional option because
of its relative lack of adverse and sedative
effects. Opioids should be reserved as a final
option, either alone or in conjunction with other
medications. A trial of oral iron therapy is
indicated for all patients with RLS, particularly
premenopausal women, as some patients without
evidence of iron deficiency may still respond
favorably.
Combination therapy is often useful, and periodic
changes in choice of medication to deal with
tolerance are frequently necessary. In some
patients, additional doses of medication may be
necessary during the day to manage diurnal symptoms.
Cost of medications The treatment plan should
include consideration of prescription costs. Typical
monthly costs will be highest for cabergoline;
intermediate for pramipexole, ropinirole, and
gabapentin; lower for levodopa/carbidopa; and lowest
for carbamazepine.
Treatment in pregnancy The treatment of RLS in
pregnant women is complicated by the fact that
nearly all of the drugs used for RLS are considered
pregnancy risk factor C or D. The one major
exception is pergolide, which has other serious side
effects. The following options are therefore
suggested: Opioids can be used in the second or
third trimester if treatment of RLS symptoms is
necessary. The lowest effective dose of opioids
should be used for the shortest period of time to
reduce the risk of neonatal withdrawal. In most
patients, RLS begins in the third trimester of
pregnancy and disappears toward the end of the
pregnancy. Oral iron supplements should be
maintained since it appears that women with RLS in
pregnancy have lower hemoglobin and mean corpuscular
volume than healthy subjects. In exceptional cases,
parenteral iron therapy is a consideration.
Nonpharmacologic therapy should be tried if RLS
symptoms occur earlier than the third trimester. Leg
stretching before sleep and use of elastic stockings
may also be helpful. Elastic stockings or
sclerotherapy should be considered if varicose veins
are prominent. The patient should be counseled
regarding the benign nature of the problem.
Most drugs for RLS are not recommended or are not
rated by the American Academy of Pediatrics (AAP)
for use during breast feeding. Codeine and
propoxyphene are considered compatible with breast
feeding but should be used with caution. |