Download The treatment challenges of restless legs syndrome

PRESCRIBING IN PRACTICE ■
The treatment challenges of
restless legs syndrome
SANJAY GANGADHARAN, LAUREN PERKINS, ANNA SAUERBIER AND K RAY CHAUDHURI
Restless legs syndrome
is
a common disorder
characterised by the
uncontrollable urge to
move the legs, particularly
during inactivity or rest.
Although the condition is
common and has a high
impact on quality of life,
diagnosis and appropriate
management remain a
challenge in the primary
care setting.
R
estless legs syndrome (RLS), also
known as Willis-Ekbom disease, is a
common sensorimotor disorder characterised by an uncontrollable urge to move
certain parts of the body, in particular the
lower limbs. It is initiated or aggravated during inactivity or rest and is mostly worse
at night time. The condition spans several
specialities including neurology (movement
disorders), sleep disorders and neuropsychiatry, and patients may also present to
haematology, nephrology or rheumatology.
Thomas Willis first described RLS in the
17th century, although references to RLS
exist in ancient Chinese and Greek literature
as well. Karl Ekbom first used the term ‘restless legs syndrome’ in 1945.1,2 He noted
the familial nature of RLS and its association with anaemia and pregnancy, the link
with vitamin B12 deficiency (related to stomach surgery)2 and the association with pain.
This is why RLS is also called Willis-Ekbom
disease.
More recently, the International RLS
Study Group (IRLSSG) validated the
IRLSSG criteria3 for diagnosing RLS and
devised the IRLSSG rating scale (mild,
moderate, severe, very severe), which is
widely used in clinical trials.4
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Country
No. of
patients
No. of
practices
Unadjusted
prevalence (%)
Adjusted
prevalence (%)
Denmark
1397
9
2.9
3.5
Germany
1360
5
2.1
2.4
Ireland
2628
19
3.2
4.6
Netherlands
2121
15
5.0
6.0
Spain
2047
10
3.9
4.6
UK
1011
4
2.8
4.6
Table 1. Prevalence of restless legs syndrome in primary care in western Europe5
Epidemiology
A primary care study from Allen et al.
investigated the prevalence rates of RLS
across six countries in western Europe.
Within the population of 10,564 patients
screened, the prevalence of RLS in people of European descent ranged from
2.4–6 per cent (see Table 1).5
RLS affects about 2 per cent of
school-aged children, 3 per cent of
30-year-olds and 20 per cent of people
aged 80 and older.5-7 Women are more
affected than men in a roughly 2:1 ratio,
with nearly one in three pregnant women
experiencing RLS during their third
trimester.6
Multiple studies on the prevalence of
RLS in non-European ethnic groups report
much lower prevalence rates, ranging from
0.1–3.3 per cent, suggesting genetic, environmental or sociocultural factors in expressivity or reporting.4,8,9 However, a recent
Korean and Argentinian study has reported
a higher prevalence rate of RLS using validated methodology; the prevalence of RLS
in Asian and Latin American populations
therefore needs further research.
RLS types
RLS can be categorised into two types:
either primary (idiopathic) or secondary.
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Restless legs syndrome
Primary RLS is the most common, with the
cause known to be sporadic or, in a minority
of cases, hereditary. Familial aggregation of
RLS is well documented and the heritability is 54–83 per cent. Concordance among
monozygotic twins is 50–80 per cent with
variable symptom expression.10
Secondary RLS, however, is related
to an underlying health condition and can
be aggravated by certain medications. At
least 20 medical conditions associated
with RLS have been reported in medical
literature. The most common medical
conditions associated with RLS include
renal failure/uraemia, depression and
Parkinson’s disease (see Table 2). 11
Vitamin B12/folate deficiency is also a
cause of secondary RLS and levels should
be checked regularly in clinical practice.
Diagnosis and assessment in
primary care
The IRLSSG updated the RLS diagnostic
criteria in 2014.12 Diagnosis of RLS can
be made if all of the following five essential criteria are met:
• An urge to move the legs usually but
not always accompanied by, or felt to be
caused by, uncomfortable and unpleasant sensations in the legs
• The urge to move the legs and any
accompanying unpleasant sensations
begin or worsen during periods of rest
or inactivity, such as lying down or sitting
• The urge to move the legs and any
accompanying unpleasant sensations
are partially or totally relieved by movement, such as walking or stretching, at
least as long as the activity continues
• The urge to move the legs and any
accompanying unpleasant sensations
during rest or inactivity only occur in
the evening or night, or are worse in the
evening or night than during the day.
• The occurrence of the above features is
not solely accounted for as symptoms primary to another medical or a behavioural
condition, eg myalgia, venous stasis, leg
oedema, arthritis, leg cramps, positional
discomfort, habitual foot tapping.
In fact, an even quicker way to screen
for RLS in clinical practice is to use the
following validated single question developed by Ferri et al: “When you try to relax
in the evening or sleep at night, do you
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Causes
RLS group n=3319
(% patients)
Control group n=3319
(% patients)
Odds ratio* (95%
CI)
Depression
512 (15.4)
420 (12.7)
1.24 (1.07–1.44)
Anxiety
275 (8.3)
241 (7.3)
1.09 (0.91–1.32)
Diabetes mellitus
140 (4.2)
206 (6.2)
0.66 (0.52–0.82)
Iron deficiency anaemia
127 (3.8)
159 (4.8)
0.77 (0.60–0.98)
Hypothyroidism
55 (1.7)
59 (1.8)
0.91 (0.63–1.32)
Pregnancy
42 (1.3)
51 (1.5)
0.84 (0.53–1.31)
Parkinsonism
32 (1.0)
21 (0.6)
1.49 (0.85–2.61)
Rheumatoid arthritis
27 (0.8)
30 (0.9)
0.95 (0.56–1.60)
End-stage renal disease
17 (0.5)
4 (0.1)
4.76 (1.59–14.3)
Fibromyalgia
10 (0.3)
8 (0.2)
1.26 (0.47–3.40)
*Odds ratio represents the odds that an outcome will occur given a particular exposure
Table 2. Reported causes and determinants of restless legs syndrome (RLS) in a UK study: occurrence in
the two years before the index date (the date of RLS diagnosis in the RLS group)11
ever have unpleasant, restless feelings in
your legs that can be relieved by walking
or movement?” This question has 100
per cent sensitivity and 96.8 per cent
specificity for the diagnosis of RLS.13
Management of RLS
Lifestyle factors that have been shown
to precipitate RLS, and therefore those
to be avoided, include: a high caffeine
intake,14 excessive alcohol in particular
at night time,15 severe stress, shift work,
poor sleep hygiene and intense physical activity near bedtime. Sleep hygiene
(including regular bedtimes, a comfortable sleeping environment as well as adequate bedding, etc) and lifestyle changes
should always be considered and tested
before any pharmacological therapy
is prescribed. An acute worsening of
symptoms can be managed with hot or
cold massage, physical activity such as
stretching or walking, mental distraction
and relaxation exercises.16
A key point to consider in the diagnosis of RLS is that the presence of RLS
symptoms does not fully translate to a
clinically significant disorder that warrants
treatment; this was demonstrated in the
REST study.17 It is the responsibility of the
clinician to determine the RLS severity
and subsequently advise on the correct
course of treatment. The IRLSSG rating
scale can be used to establish the severity of RLS, and subsequently the need for
treatment12 as well as to monitor disease
progression. A score of 1–10 represents
mild, 11–20 moderate, 21–30 severe and
31–40 very severe disease.
Although sudden remission of symptoms has been described; in most cases,
primary RLS typically runs a chronic
course with worsening of symptoms over
time. However, in secondary RLS, treatment of the underlying pathology (such
as systemic iron deficiency) can help
achieve remission of symptoms.18 Only
10–15 per cent of patients with RLS have
symptoms severe enough to be treated
with medications.17.
Dopamine agonists are the first-line
treatment for RLS. In the UK, immediate-release (pramipexole and ropinirole)
and transdermal (rotigotine) preparations are the only dopamine agonists
licensed for treatment of RLS (see Table
3). However, prolonged-release pramipexole and ropinirole are usually administered as a single evening dose, whereas
transdermal rotigotine patches have
the advantage of a sustained release
throughout the day.
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Restless legs syndrome
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Diagnosis of RLS (IRLSSG criteria)
Single screening question
Investigations
• Physical examination
•B
lood test: iron studies (serum ferritin), full blood count, serum vitamin B12/folic acid,
serum glucose and HbA1c, urea and electrolytes, serum creatinine, thyroid function
test (optional)
• Exclude co-morbidities, pregnancy and related medications
• Severe RLS, insomnia and periodic limb movements: consider sleep studies
Establish the severity of RLS
IRLSSG rating scale (mild, moderate, severe, very severe)
Does the adult patient have primary or secondary RLS?
Are their symptoms painful?
Secondary RLS
Primary RLS
Mild to moderate:
lifestyle changes,
eg sleep hygiene
Moderate to very
severe: treatment
needed (see Table 3)
Painful RLS and
neuropathic pain:
alpha 2-delta ligands
(pregabalin, gabapentin)
and opioids
Treatment of
the underlying
pathophysiology
Figure 1. Management pathway for restless legs syndrome (RLS) following a diagnosis using the International RLS Study Group (IRLSSG) criteria
Second-line treatment options for RLS
include gabapentin, pregabalin, clonazepam and opiates (see Table 3); their
use is usually guided by neurologists.
Trenkwalder et al. demonstrated that prolonged-release oxycodone and naloxone
(Targinact) was efficacious for short-term
management of severe RLS in subjects in
whom first-line therapy had failed.19 This
drug combination is now licensed in the
UK for patients suffering from RLS for
at least six months, and in whom dopaminergic treatment has already failed. It
would be most suitable for those patients
with a painful variant of RLS who have not
responded well to first-line therapies.
Because of the high rates of augmentation (see below), levodopa is not typically recommended for daily treatment
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in the UK. In individual cases, it might
be useful as a rescue medication for
patients with predictable RLS.
Complexities of RLS treatment
Augmentation is characterised by an overall increase in symptom severity while on
treatment. This is mostly seen in patients
treated with levodopa or dopamine agonists (highest rates with pramipexole and
lowest with rotigotine).20 The predictors
for augmentation include: low plasma ferritin levels, longer treatment duration, possibly a preceding tolerance to medication
and previous episodes of augmentation.20
Early morning rebound is the reappearance of symptoms of RLS when the
medication effects wear off. It is common
in drugs with a shorter half-life, such as
levodopa. Here, the practitioner should
consider altering the time of treatment
administration, increasing the drug dose
or trying an alternative drug.
Burden of RLS
Moderate or severe RLS has a high impact
on the health and wellbeing of individuals
affected, their partners and the community. Recent studies have suggested that
patients also suffer from nonmotor symptoms (NMS) such as depression, anxiety
and sleep disturbances. These NMS are
known to impact upon patients’ health-related quality of life (HRQoL), and therefore
Professor Chaudhuri’s team are leading a
project to further investigate these NMS,
including the development of a questionnaire. The biopsychosocial and economic
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■ PRESCRIBING IN PRACTICE l Restless legs syndrome
Medication
Starting dose–maximal
recommended dose
(daily)
Time to full effect
of the therapeutic
dose
Half-life
Side-effects
Pramipexole
0.088mg–0.54mg (base) or
0.125mg–0.75mg (salt)
At first dose
8–12 hours
Augmentation, impulse control disorder,
hypotension, dizziness, headache, somnolence
Ropinirole
0.25mg–4mg
4–10 days
6 hours
Same as pramipexole
Rotigotine
transdermal patch
1–3mg/24 hours
1 week
5–7 hours
Skin irritation, low risk of augmentation,
nausea, hypotension, dizziness, headache,
nasal congestion
Targinact (prolongedrelease oxycodone/
naloxone)
5mg/2.5mg–
60mg/30mg
1 week
1 hour
Headache, somnolence, nausea, fatigue
Levodopa
50mg–200mg
At first dose
1.5–2 hours
High rates of augmentation and loss of
efficacy with rebound phenomena
Pregabalin
25–300mg
3–6 days
10 hours
Sleepiness, dizziness, headache and fluid
retention
Gabapentin
300mg–2700mg
3–6 days
5–7 hours
Sleepiness, dizziness and fluid retention
Carbamazepine
100mg–600mg
1–2 weeks
16–24 hours
Fatigue, urticaria, vomiting, nausea,
dizziness and leucopenia
Clonazepam
0.5mg–2.0mg
At first dose, effect
mainly on sleep
30–40 hours
High risk of sleepiness, dizziness, morning
drug handover
Tramadol
50mg–100mg
At first dose
6 hours
Dizziness, nausea, sweating, constipation
and fatigue
Oxycodone
2.5mg–25mg
At first dose
4–5 hours
Constipation, nausea and vomiting
Ferrous sulfate
200mg three-times daily
2–3 weeks
Licensed treatments
Unlicensed treatments
Constipation
Table 3. Pharmacological treatment options for restless legs syndrome: recommended dosages, pharmacokinetics and possible side-effects. Adapted from
Klingelhoefer et al.18
burden of RLS symptoms has also been
shown to have a negative impact on the
sufferer’s HRQoL.4 Poor HRQoL leads to
decreased productivity, increased absenteeism and unemployment.21-23
Conclusion
RLS is a common sensorimotor disorder
with well-defined diagnostic criteria including a validated single screening question,
as well as full IRLSSG criteria. Early diagnosis, accurate assessment of severity and
appropriate management of the symptoms
of RLS in the primary care setting remains
20 ❚ Prescriber September 2016
a challenge, due to the complexity and heterogeneity in the disease presentation.
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Declaration of interests
Sanjay Gangadharan, Lauren Perkins
and Anna Sauerbier have no conflicts
of interest. Professor Chaudhury has
previously received an honorarium from
Mundipharma.
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Sanjay Gangadharan is an advanced
trainee in the Department of Geriatric
Medicine, John Hunter Hospital,
University of Newcastle, Australia;
Lauren Perkins is a senior research
co-ordinator, King’s College Hospital
NHS Foundation Trust; Anna Sauerbier
is a clinical research fellow and K Ray
l PRESCRIBING IN PRACTICE ■
Chaudhuri is professor of movement
disorders at the National Parkinson
Foundation International Centre of
Excellence, King’s College London; and
the Department of Basic and Clinical
Neuroscience, The Maurice Wohl Clinical
Neuroscience Institute, King’s College
London