RESTLESS LEGS SYNDROME
(RLS)
Symptom Derived Treatment
Philip M. Becker, M.D.
Medical Director, Sleep Medicine Institute, Presbyterian Hospital
Clinical Professor, Dept. of Psychiatry, UT Southwestern Medical Center
Dallas, Texas
Patients describe RLS in a multitude
of colorful ways
A compelling sensation occurring at
rest that creates URGE to move.
Described, often with difficulty or in
dramatic terms, as:
"creepy, crawly, jumpy"
"heebie jeebies"
"jerky or jittery"
"ants or worms crawling inside"
"agitation, anxious" but just in the limbs
(unless very severe)
"hurts deep inside but it isn't really pain"
IRLSSG Diagnostic Criteria
Four Core Symptoms are required
“U R G E”
U = Urge to move the limb(s)
R = Rest worsens the sensation
G = Get up & Go is Good
(temporary relief with movement)
E = Evening / night worsening
Current Hypothesis on Etiology
• Dopaminergic Mechanism in RLS
– Success of dopaminergic therapy supposes a mechanism of
action.
– Four studies have identified small reductions (10-20%) in
striatal dopamine activity.
• Iron Dysregulation in the CNS
– Conner et al. found reduced iron transporter in nigral neurons of
RLS patients compared to control brains.
– Serum ferritin less than 30 increases the likelihood of improvement
with iron.
– CSF ferritin reductions correlate with RLS severity.
– Iron stores in the substantia nigra of RLS patients are lower on fMRI.
Epidemiology of RLS
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Primary Restless Legs Syndrome
presents generally before age 30.
Etiology of primary RLS is unknown.
About 50% of primary patients have a
positive family history for RLS.
Genetics:
• Trenkwalder: probable autosomal dominant inheritance
with high penetrance and variable expressivity.
• Desaulters: Chromosome 12q in French-Canadians
There must be no medical or substances to account
for the symptoms.
Secondary RLS arises
more commonly after age 30.
It arises in or from other conditions
such as:
Uremia
23 - 30% report RLS
Pregnancy 17% report RLS
Neuro Disorders: spinocerebellar ataxia, CMT 2,
Small fiber neuropathy, DM, lumbar radiculopathy
Metabolic Deficiency: IRON, folate, B12,
thyroid, others
Rheumatoid Arthritis
Treatment focuses upon correction of
the medical disorder.
Management Strategies for RLS
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Target Symptoms
for RLS Therapy
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Behavior Modification for RLS
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Pharmacologic Treatment Experience
for RLS
• Opiates
• Benzodiazepines
300 + years
25 + years
• Clonazepam & others
• Levodopa
• Dopamine Agonists
15 + years
5-10 years
• Ropinirole, pramipexole, others
• Anti-convulsants
5 + years
• Gabapentin
• Others (iron, mg, calcium, B vitamins, magnets, etc.)
Complex RLS Case
• 54 y/o W/M man with 20+ year hx of RLS.
• Renal disease with creatinine of 2.1, stable.
• Hospitalized for major depression 4 yrs ago; currently
taking fluoxetine at 40 mg/d.
• “My legs are driving me nuts. Inside they crawl and hurt.
I just have to move them.”
• “I can’t live this way any longer. I would be better off
dead.”
• Taking carbidopa/levodopa ER 50/200 qid for 8 months.
Relief of 1-2 hours, otherwise 24-hour RLS.
Treatment Planning for WM
 Did anything help you? “I slept with Percodan
(taken for 3 days after dental work).
 Sinemet CR “helped for 2 months and then it
won’t last. I took more.”
 Do you have a plan to take your life? “No, I
love my kids. It wouldn’t be fair to them.”
 Recheck creatinine, hemoglobin and
hematocrit, B12, folate, and Ferritin. No
changes were found.
WM has
Augmentation to Levodopa
• Augmentation: shift of RLS symptoms by two or
more hours to an earlier onset compared to the
patient’s baseline.
• Levodopa produces augmentation in 30-85% of RLS
patients (Ave onset: 1-3 months).
• Dopamine agonists (DA) estimated to produce
augmentation in 15-35% of patients (Onset >6 mos).
• Management Options:
• For levodopa, taper off then switch to DA.
• If DA, consider earlier dosing. Observe for further
augmentation.
• In the severe patient, shift to high potency opiate.
• Consider gabapentin, clonazepam or other therapy.
Initial Treatment Plan for WM
 Taper carbidopa/levodopa ER 50/200 by one tablet
every 2 days, beginning at h.s., to prevent
augmentation.
 To reduce augmentation, substitute ropinirole 0.25
mg for each of the c/l dopa ER tablets every 2
days.
 Oxycodone 5 mg p.o. h.s. for acute symptom relief
and to improve sleep.
 Emphasized complexity, need for daily contact
and possible need to hospitalize.
Comparison of Dosing of
Dopaminergic Agents for RLS
Agent
Brand
Name
Initial
Dose (p.o.)
in mg
Dosage
Timing
(h.s. RLS)
Dosing
Adjustment
Recom.
Maximum
Dose (mg)
levodopa
Sinemet &
others
25/100
1/2 - 1
@ h.s.
1 q 3d
300*
(total)
C/Ldopa ER
Sinemet CR
25/100
1
1 q 3d
earlier pm
300*
(total)
pergolide
PERMAX
0.05
pramipexole
MIRAPEX
ropinirole
REQUIP
2hr b4 h.s.
1 q 2-3d
1-2
0.125
1 supper
&/or h.s.
1 2hr b4 hs
1 q 2-3 d
1.5 - 3
0.25
1
1 q 2-3 d
4-8
1-2hr b4 h.s.
*Levodopa maximum of 300 mg recommended to lessen augmentation. Up to 1200mg/ d has been used.
WM Treatment Course
Day 1-10
Day 1: “I slept 5 hours.”
Day 6: “The legs are 30% better, but I’m
only sleeping 4 hours or so.”
Response: INCREASE ROPINIROLE
DOSES #3&4 to 0.50 mg.
Day 10: “My legs are OK until about 11:00
and then they act up. The medicine makes me
really sick (nauseated).”
Response: Nausea should get better. (I wish
domperidone was available in U.S.)
INCREASE ROPINIROLE at noon to 0.5 mg.
Limitations to
Therapeutic Benefit

Side effects
Dopamine agonists: nausea, edema, myalgia,
sleepiness, insomnia, augmentation
Opioids: sleepiness (? SDB), insomnia,
constipation, nausea, “fear of addiction”

Loss of efficacy
Consider anemia/iron deficiency.
Need for dose adjustment
Is it augmentation?
WM Treatment Course
Day 11-14
Day 11: “I’m sick all day. I didn’t sleep.”
Response: Discontinue a.m. ropinirole.
Day 12: “You got to do something.”
Response: Reduce ropinirole to 0.25 mg noon
& 6:00 pm, continue 0.5 mg at 10:00 pm.
Day 14: “I’m not as sick but my legs are
worse. Is this ever going to get better?”
Response: Add oxycodone 5 mg at 6:00 p.m.
(and h.s.). Reduce ropinirole to 0.25 mg TID.
WM Treatment Course
Day 21-24
Day 21: “I’m 50 % better. I even slept 6
hours one night.” RL starts at about noon.
Response: Increase ropinirole to 0.5 mg with
lunch.
Day 24 “That stuff makes me sick. I
decreased it (back to 0.25 mg at noon). My
legs were getting puffy.”
Response: Checked chemistries and renal
function. No acute changes.
WM Treatment Course
Day 26-35
 Day 26: “Doc, I think the dope works the best.
The fluid was making my legs hurt.”
 Response:
Stopped ropinirole
Changed oxycodone to METHADONE 5 mg at
6:00 p.m. and 10:00 p.m.
Day 35: “Doc, it’s amazing. I don’t feel
my legs jumping and I slept for five nights
straight.” Edema resolved.
Efficacy of Different Opioids
in Treatment of RLS in 18 Severe Patients
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WM Treatment Course
Day 35 +
• Depression remained moderate with low energy &
motivation; moderate sadness.
• WM’s personal doctor agreed to my request
to discontinue Prozac.
• Wellbutrin SR 150 mg was started and increased
to a.m. and noon one week later.
• Four weeks later, clonazepam 0.5 mg h.s. was
added due to “feeling a bit nervous.”
• At eight weeks, he slept >6 hours nightly and said
“I feel pretty good.” He has remained so for 3+
years on methadone, buproprion XL and
clonazepam.
Treatment Considerations
for Restless Legs Syndrome
• Treat symptoms identified as problems by patient.
• Dopamine agonists are the first line, presuming a
ferritin > 30. Target therapy before RL onset.
• C/L dopa causes augmentation. Best used prn.
[Arbitrary limit:300 mg/week ( 3 tabs of 25/100)]
• Opiates restore severe patients. High potency
agents preferred (methadone, levorphanol, hydromorphone) but
caution for EDS and SDB.
• Gabapentin is variably effective. Best with “pain”.
• Depression and anxiety are common and require
treatment when present. Buproprion preferred.