Thomson

Review
Pharmacological management of symptoms in multiple

sclerosis: current approaches and future directions
Alan J Thompson, Ahmed T Toosy, Olga Ciccarelli
Lancet Neurol 2010; 9: 118299
Department of Brain Repair
and Rehabilitation, UCL
Institute of Neurology,
University College London,
London, UK
(Prof A J Thompson FRCP,
A T Toosy PhD, O Ciccarelli PhD)
Correspondence to:
Dr Olga Ciccarelli, UCL Institute
of Neurology, University College
London, Queen Square,
WC1N 3BG London, UK
o.ciccarelli@ion.ucl.ac.uk
1182
Management of symptoms in multiple sclerosis (MS) has received little attention compared with disease-modifying
treatments. However, the eect of these symptoms on quality of life can be profound. Clinical trials of pharmacological
drugs to treat symptoms of MS have often been underpowered and have used inappropriate measures of outcome.
Many currently used symptomatic drugs were introduced decades ago, when study quality was considerably below
current standards. Therefore, the evidence base on which to make clinical decisions is less than adequate. Interest in
pharmacological treatment of symptoms in MS has increased in recent years, and several large randomised controlled
trials have been reported. Pharmacological strategies are a core component of the treatment of these symptoms, but
it is imperative to remember that a multidisciplinary rehabilitation approach is needed for eective management.
Introduction
Multiple sclerosis (MS) has a substantial economic and
social burden. The total nancial cost per patient per year
has been estimated at about US$48 000 in the UK in
2007, with a lifetime cost of $12 million.1 People with
this disorder can have many disabling symptoms that
result in high emotional, psychological, and physical
burden for the patients and carers. Therefore, the
eective management of symptoms of MS is crucial,
since it can improve quality of life, reduce the eect of
disability on daily activities, and help patients to continue
employment or education.
Pharmacological treatment is an essential component
in the management of symptoms of MS and a patientcentred approach is central to its success. Physicians
need to educate patients appropriately, discuss their
priorities and expectations, and help them to select the
right treatment to optimise compliance, especially with
invasive interventions. Symptoms can change during
the course of the disease; hence serial monitoring helps
to optimise interventions. With oral drugs, the initial
dose should be low and increased slowly according to
response and tolerability. If one drug is insucient
because it is partially eective or has intolerable sideeects, then a combination of drugs, perhaps at lower
doses, is advisable.
In this Review, we will describe pharmacological
treatments for these symptoms, which represent an
important component of a multidisciplinary approach
to improve quality of life, ease care, and ensure
independence. Surgical interventions will also be covered
where relevant, but rehabilitation approaches such as
physiotherapy are beyond the scope of this Review and
are mentioned only briey. Some recent large and well
conducted trials that have assessed the ecacy of
symptomatic medications such as fampridine2 and
cannabinoids3 represent a clear improvement in the
quality of trial design. Future trials of good quality should
provide a strong evidence base for identication of
optimum treatments. In the meantime, in this Review,
we provide an update on the available evidence for
optimum treatment of symptoms in MS, discuss the
issues that need to be addressed before starting treatment,

and provide recommendations for the most appropriate
drug treatments.
For the management of individual symptoms, we
group the wide range of symptoms of MS, beginning
with mobility-related symptoms, such as spasticity,
ataxia, and impaired ambulation. We then discuss
bladder, bowel, and sexual dysfunction. The next group,
which is often overlooked despite being very disabling
for patients, consists of fatigue, cognitive dysfunction,
and mood disturbance. These symptoms can interact, as
can their treatments. This is also true for pain, another
overlooked symptom discussed here. Finally, we will
briey discuss symptoms resulting from visual and
brainstem involvement.
Mobility-related symptoms
Spasticity
Spasticity is seen in more than 60% of patients with MS.
This increased muscle tone (or hypertonia) results from
injury to the corticospinal system and unmodulated
activity of local spinal neurons and sensory aerent
pathways. If not well managed, it can lead to pain,
spasms, reduced mobility, limited range of movement,
and contractures.
General management
At the outset, several issues need to be considered. First,
is spasticity localised or generalised? Localised spasticity
is amenable to physiotherapy and stretching of specic
muscles, splinting, and botulinum toxin. Conversely, for
generalised spasticity, oral drugs and, at a later stage,
intrathecal interventions are commonly considered.
Second, are there features that could aect the patients
function, such as spasms (which can be painful),
clonus, muscle shortening, and tendon or soft tissue
contractures? Third, is spasticity masking underlying
muscle weakness and ataxia? Individuals might rely on
spasticity to walk or stand. Increased weakness and
deterioration of tremor and coordination are sometimes
reported side-eects of anti-spasticity medications,
resulting from the reduction in muscle tone. Fourth, are
www.thelancet.com/neurology Vol 9 December 2010
Review
there aggravating factors? Urinary and bowel dysfunction,

poor posture or positioning, and pressure sores can
exacerbate spasticity. Pain of dierent origins (central
pain, back pain, pain originating from unrecognised
fractures) also needs to be considered. Addressing these
factors is essential before pharmacological treatments
are considered. Fifth, which drug treatments are
appropriate? If drug therapy has already started,
optimisation of its dosage or timing of administration
might be necessary. Finally, are physiotherapy and
nursing interventions available? The physiotherapist
works with the patient to follow a mutually agreed, goaloriented programme with the aim of improving patient
function and quality of life. In cases of acute deterioration
after a relapse, or of rapid progression, physiotherapy
input is often needed to reduce spasticity and improve
mobility and independence. Nursing intervention is
essential to tackle precipitating and aggravating factors,
such as pressure sores and ingrown toenails.
Pharmacological treatments
The evidence base for drugs commonly used to treat
spasticity in MS is poor; trials are rare and many are
underpowered, are unblinded, and use poorly validated
measures (table 1). Trials generally use the Ashworth
scale as the primary outcome measure of spasticity, but
this has limitations14 such as poor reliability, validity,
and responsivenessall potential disadvantages of oneitem scales.
Baclofen, benzodiazepines (ie, diazepam and
clonazepam), and tizanidine seem to have similar
eects in reduction of stiness and spasms,4,13 but
tizanidine seems to be the best and diazepam the worst
tolerated.15 Although baclofen has been extensively
investigated, its ecacy has not been well proven
(table 1). The initial dose should be low and increased
slowly, although high doses tend to be tolerated
reasonably well.16 In clinical practice, baclofen is
recommended as the rst choice, especially in patients
with spinal cord-related spasticity. Tizanidine can also
be used as a rst-line treatment, although both well
designed positive5,6 and negative7 trials have been
published (table 1); side-eects are dose-dependent.6
Clonazepam can help reduce spasms and stiness.
This drug should be prescribed at night because of
drowsiness, and alone or in combination with baclofen
or tizanidine; this strategy increases its tolerability.
Second-line drugs include gabapentin and dantrolene.
The use of gabapentin in treatment of spasticity and
spasms in MS is increasing, despite weak evidence of its
ecacy from small trials (table 1);9 it is well tolerated and
can be particularly useful when central pain coexists
(table 1). Dantrolene can be eective in treatment of
spasms and clonus rather than stiness; however, it has
a poor safety prole (table 1) and data on its ecacy are
scarce, with only a few very small studies. Another
possible second-line drug is tolperisone, although it has
been tested only in patients with spasticity after stroke.17

The results of this randomised double-bind placebocontrolled trial17 in 120 patients showed that tolperisone
reduces spasticity eectively, as measured by the
Ashworth scale, and is well tolerated.
Cannabinoids are the most innovative drugs for
spasticity and, after improving spasticity and tremor in
animals,18 they were tested in patients with MS in a large
placebo-controlled trial3 with 1-year follow-up10 (table 1).
These trials3,10 were aected by the limitations of the
Ashworth scale, diculties with blinding attributable to
the psychoactive side-eects, and a strong placebo eect.
More studies are needed to conrm the potential benets
of cannabinoids with better validated spasticity scales,
incorporating the patients perspective.19 From a
pragmatic point of view, cannabinoids can be helpful
when spasticity is associated with central pain. An
oromucosal spray (Sativex; GW Pharmaceuticals,
Wiltshire, UK) containing dronabinol (delta-9 tetrahydrocannibinol) and cannabidiol (CBD), has become
available for use as an add-on treatment for MS-related
spasticity that is not adequately controlled with other
available treatments; if there is no benet at 4 weeks, the
treatment can be stopped.20
Intrathecal baclofen is recommended for patients
with severe spasticity that is dicult to manage with
oral drugs. It is given through a catheter that releases
the drug directly into the intrathecal space from a
programmable pump in the abdominal wall. Thus, very
high concentrations can be achieved without systemic
side-eects. Benecial eects are seen with spasticity
and muscle spasms,21 life comfort, pain,22 sleep time,
and periodic leg movements.23 The dose of baclofen
needs empirical calibration and adjustment at regular
intervals. Interestingly, after a period of clinical stability, paradoxical unresponsiveness to baclofen with
increased dose has been described.24 The most common
complications relate to pump malfunction and technical
problems with the catheter; an increased risk of epileptic
seizures and non-convulsive status epilepticus in
treated patients compared with matched controls has
also been described.25 Intrathecal baclofen seems to be
safe in pregnancy, and possibly safer than oral baclofen
for the newborn.26 When severe pain remains a
problem despite treatment with intrathecal baclofen,
then morphine can be added.27 Intrathecal phenol is an
eective alternative to intrathecal baclofen in patients
with severe spasticity to improve spasms and pain, but
it can aect urinary and bowel continence.28 In our
experience, this drug can be used to improve care and
posture in severely disabled patients who have lost
bowel and bladder function and have absent sensation
in the lower limbs.
Botulinum toxin A is recommended to induce muscle
relaxation and prevent contractures in distal muscles
and in selected proximal muscles such as hip adductors.29
In general, larger muscles are treated, which means that
1183
Review
there is no need for electromyographic guidance. The

treated muscle is paralysed by neuromuscular
transmission block.30 The advantages of this therapy
include minimum systemic side-eects and the nonMain results
daily regimen. However, its eect disappears after

36 months, depends on the target muscle and injected
dose, and has a high cost. Its benet is enhanced if
combined with a physiotherapy and stretching exercise
Action
Daily doses in
clinical
practice
(minmax)
Most common side-eects

in clinical practice
Study design
Main outcome measures
Cochrane review
(26 placebo-controlled
studies and
13 comparative studies)
3 of 8 placebo-controlled trials
Ashworth scale (15 studies);
spasms, other symptoms, and showed a signicant dierence
between groups
overall impression
Binds the GABAB receptor,

causing inhibition of the
excitatory activity of spinal
reexes
10120 mg
Sedation, drowsiness, muscle

weakness, paraesthesia,
gastrointestinal symptoms,
hallucinations, and seizures
UK Tizanidine Trial5 Double-blind

randomised
placebo-controlled
study; 187 patients
Ashworth scale; activities of

daily living
Tizanidine reduces spasticity

compared with placebo; no
improvements in activities of
daily living
Exact mechanism of
action remains unknown;
its main activity is thought
to occur at a presynaptic
level by reducing release of
excitatory aminoacids
636 mg
Fatigue, tiredness,
somnolence, dizziness,
drowsiness, dry mouth,
postural hypotension, and
liver function abnormalities,
which improve after
discontinuation; these
side-eects increase with
increasing drug
concentrations in plasma6
Nance et al6
Double-blind
randomised
placebo-controlled
dose-response study;
142 patients
Ashworth scale; knee-swing

amplitude using pendulum
test
Positive eect of tizanidine on

spasticity related to plasma drug
levels
See above
See above
See above
Smith et al7
Multicentre
double-blind
randomised
placebo-controlled
study; 220 patients
Ashworth scale; type and

frequency of muscle spasms
(patients diaries)
No dierences in spasticity
between groups; greater
reduction in spasms in treated
group compared with placebo
group
See above
See above
See above
Mueller et al8
Double-blind
placebo-controlled
crossover study;
15 patients
Ashworth scale; Kurtzke

disability scale; visual faces
scale rating, quantitative
surface electromyography,
clonus and reex withdrawal,
Babinski response
Signicant dierences on the

Ashworth scale, visual faces scale,
and Kurtzke disability scale
between groups
Decreases glutamate
concentrations released
from presynaptic
terminals
300 mg
3600 mg
Drowsiness, somnolence,
dizziness, and gastrointestinal
symptoms
Cutter et al9
Double-blind
placebo-controlled
crossover study;
22 patients
Modied Ashworth scale;

expanded disability status
scale; clonus scale, deep
tendon reexes, plantar
stimulation response, spasm
frequency and severity scales,
interference with function
scale, painful spasm scale, and
global assessment scale
See above
Signicant dierences on the
Ashworth scale, plantar
stimulation response, spasm
severity scale, interference with
function scale, painful spasm
scale, and global assessment scale
between groups
See above
See above
Zajicek et al3
Multicentre
double-blind
randomised
placebo-controlled
study; 630 patients
Ashworth scale; other

secondary outcome scales;
patient-reported spasticity
and pain
No dierence on the Ashworth

scale between groups;
improvements in patientreported spasticity and pain in
the treated group
Probably interacts via

cannabinoid receptor
type 1 expressed in CNS,
leading to inhibition of
neurotransmitter release
NA
NA
Zajicek et al10
Double-blind 1-year
follow-up study;
502 patients
Ashworth scale
Signicant eect on spasticity on

the Ashworth scale in the group
treated with dronabinol
See above
NA
NA
Wade et al11
Double-blind
randomised
placebo-controlled
study; 160 patients
Ashworth scale; visual

analogue scale score for
spasticity (subjective measure
recorded in patients diaries)
No dierence in spasticity on the

Ashworth scale between groups;
signicant improvement on the
visual analogue scale score for
spasticity
See above
NA
NA
Baclofen
Shakespeare et al4
Tizanidine
Gabapentin
Cannabinoids
(Continues on next page)
1184
Review
programme.31 A trend exists towards increased ecacy

and duration of eect, with increasing doses.29 However,
the dose that can be injected can reach a maximum,
after which the patient is at greater risk of developing
systemic botulinum toxicity. Botulinum toxin can be
combined with other treatment modalities, such as oral
baclofen and physiotherapy under expert clinical
guidance.
Ataxia and tremor

Little evidence exists for the treatment of ataxia and
tremor, which are symptoms that remain very
challenging to manage. Up to 80% of patients with MS
have tremor or ataxia in the duration of their disease.32
Ataxia consists of a reduction in coordination in one (or
more) limb, trunk and gait, and can be caused by
dysfunction of the cerebellum (cerebellar ataxia) or
sensory system (ie, caused by impaired proprioception).
Cerebellar ataxia is often associated with tremor,
which usually occurs during voluntary movements or
during the maintenance of a position. Tremor is a
frequent symptom of MS, and has been detected in more
than half of patients attending specialist MS clinics.
Clinical trials have been small, limited by inadequate
design and outcome measures, and essentially negative
(table 2).32 Although recommendations are dicult to
make for the treatment of ataxia and tremor, we have used
propanolol,35 clonazepam, levetiracetam,40 isoniazid33,34
(limited by side-eects), and carbamazepine.41 Other drugs
tested include ondansetron (reported to improve tremor
in the rst trial36 but not in a subsequent open-label
study37), dolasetron,38 cannabinoids,39 and glutethimide.42
Larger randomised controlled trials of interventions that
Study design
address these disabling symptoms with scientically

sound outcome measures are urgently needed.
Surgical interventions
Carefully selected patients with localised tremor with
minimum disability could benet from stereotactic
thalamotomy, which targets the nucleus ventralis lateralis
and nucleus ventralis intermedius, or deep brain
stimulation, which targets the nuclei ventralis lateralis
and nucleus ventralis intermedius, ventralis oralis
posterior nucleus, and zona incerta.4345 Stereotactic
thalamotomy seems to be more eective for intractable
tremor, but the consequent functional improvement is
variable and the intervention is associated with a higher
risk of neurological decit. Deep brain stimulation is
likely to improve tremor, but the eect might be reduced
over time. Functional improvement is more often
reported after deep brain stimulation than after
stereotactic thalamotomy, and deep brain stimulation
can be better tolerated. However, the choice between
interventions should be made on an individual basis in
consultation with the specialist neurosurgical team. In
our experience, distal tremor with good proximal stability
and limb function are particularly responsive to deep
brain stimulation. However, larger trials that compare
these two interventions and assess the ecacy of gammaknife thalamotomy46,47 are needed.
Impaired ambulation
Physiotherapy input should always be considered when
ambulation disability develops after a relapse or when it
is associated with rapid progression. The aminopyridines
have been extensively investigated in the context of this
symptom. Initial studies did not convincingly show
benecial eects on ambulation.48 However, recent
Main results
Action
Daily dose
(minmax)
(Continued from previous page)

Comparative trials
Eyssette et al12
Multicentre randomised
double-blind study of
tizanidine vs baclofen;
100 patients
Functional status (walking

distance), patients state in
bed and in a chair, exor
spasms, stretch reex, angle
at which contracture occurs
No dierence between the two

drugs
NA
NA
NA
Groves et al13
Meta-analysis of
10 double-blind
randomised studies of
tizanidine vs baclofen
(7 studies) or diazepam
(3 studies);
270 patients*
Ashworth scale; muscle

strength and global
tolerability to treatment
rating
All three drugs had a similar eect NA

on spasticity; tizanidine seemed
to be better tolerated
NA
NA
This table includes studies that were considered to be important in terms of results and are characterised by acceptable study designs, in accordance with the scope of this Review. Preference was given to more
recent trials. The information given on action, dose, and side-eects is based on all the articles read for the preparation of this Review, on the drug leaets, and on the authors own experience. Clonazepam
(0252 mg; generally one dose at night) and dantrolene (25400 mg) can also be used for treatment of spasticity but evidence for their ecacy is weak. Side-eects for clonazepam include drowsiness, fatigue,
sedation, reduced attention, poor concentration, memory problems, dependence, and withdrawal; side-eects for dantrolene include gastrointestinal symptoms, CNS symptoms, muscle weakness, and
hepatotoxicity, which is important to remember. Min=minimum. Max=maximum. NA=not applicable. *Also included patients with cerebrovascular diseases.
Table 1: Selected studies and reviews of anti-spasticity drugs in MS
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studies of long-acting 4-aminopyridine (fampridine) have

shown positive results for this drug on walking ability in
a proportion of patients.2 In a large double-blind
controlled phase 3 trial,49 229 patients were treated with
sustained-release oral fampridine 20 mg a day, which
was previously shown to be the safest dose, and 72 patients
were treated with placebo. A higher proportion of
responders, as dened on the basis of repeated
standardised assessments of the timed 25-foot-walk test,50

was seen in the fampridine group than in the placebo
group.2 Additionally, timed-walk responders showed
reduced self-assessed ambulation-related disability, as
measured by the 12-item MS walking scale,51 compared
with non-responders. However, the proportion of timedwalk responders was only 35% (vs 8% in the placebo
group), and walking speed improved by only 25% in the
Study design
Main results
Hallett et al33
Double-blind placebo-controlled crossover trial;

6 patients
Self-rating scales, quantitative tremor

recording, blinded ratings of videotapes
All patients improved on at least one outcome measure
Duquette et al34
Open-label study; 13 patients with MS and tremor
Patient assessment, blinded rating of

videotapes
10 patients showed improvement
Double-blind placebo-controlled randomised crossover

study of propanolol, ethanol, and isoniazid; 3 patients
with MS and 3 patients with idiopathic cerebellar tremor
Writing tasks, self-assessment, clinical

examination, accelerometry
No eect for any treatment
Rice et al36

study; 20 patients with tremor (16 with MS)
Writing tasks, self-assessment, nine-hole

peg test
12 of 16 patients with MS showed tremor reduction
Gbadamosi et al37
Open-label prospective study; 14 patients with MS and

tremor
Writing tasks, self-assessment, nine-hole

peg test
No treatment eect

study; 34 patients with MS and tremor
Nine-hole peg test, ataxia scores
No treatment eect

study; 14 patients with MS and upper limb tremor
Tremor rating scale
No treatment eect

study; 18 patients with MS and intention tremor
Fahns tremor rating scale A and B
No treatment eect
Single-blind placebo-controlled randomised study;

10 patients with tremor (7 with MS)
Tremor rating scale, accelerometry
All 7 patients with MS improved
Open-label study; 8 patients with tremor (6 with MS)
Computer-assisted tracking task, blinded

assessment by occupational therapist
5 of 6 patients with MS improved
Isoniazid
Propanolol and ethanol

Koller35
Ondansetron
Dolasetron
Monaca-Charley et al38
Cannabinoids
Fox et al39
Levetiracetam
Feys et al40
Carbamazepine
Sechi et al41
Glutethimide
Aisen et al42
Thalamic stimulation or surgical thalamotomy

Bittar et al43
Comparative study of thalamotomy vs thalamic DBS;

20 patients with MS and intractable tremor
Clinical tremor rating scale
Postural tremor improved by 78% for thalamotomy vs

64% for DBS (p>005); intention tremor improved by
72% for thalamotomy vs 36% for DBS (p<005); more
adverse eects for thalamotomy than for DBS (30% vs 10%)
Schuurman et al44
Randomised controlled study of thalamotomy vs DBS;

68 patients with drug-resistant tremor (10 with MS)
Clinical tremor and functional rating scales
Functional status improved more with DBS than with

thalamotomy but tremor improved equally for both; fewer
side-eects for DBS; for patients with MS, both groups had
improved tremor (DBS slightly more than thalamotomy) but
not improvements in functional state
Schuurman et al45
Observational follow-up study of Schuurman et al;44

6 patients with MS at 5 years follow-up
Functional and tremor rating scales
Reduced eect of DBS but sample size too small to make

meaningful inferences
Gamma-knife thalamotomy
Niranjan et al46
Open-label study; 8 patients with essential tremor

(3 with MS); contralateral VIM nucleus targeted
Tremor rating scale, self-assessment for

functional improvement
Improvement in all 3 patients with MS (and tremor arrest in

6 of 8 patients with essential tremor)
Mathieu et al47
Observational study; 6 patients with MS and tremor;

contralateral VIM nucleus targeted
Tremor and functional rating scales
Tremor improved in all 6 patients; functional improvement

in 4 patients
This table includes studies that are considered to be important in terms of results and are characterised by acceptable study designs, in accordance with the scope of this Review. Preference was given to more
recent trials. DBS=deep brain stimulation. VIM=ventralis intermedius nucleus. MS=multiple sclerosis.
Table 2: Selected studies and reviews of anti-tremor interventions in MS
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responder group. Clinically, it might not be easy and

feasible to identify the responders.52 Nonetheless, the
absence of any comparable drug in this area will
encourage its use in patients who do not have a history
of seizures (or epileptiform activity on a screening
electroencephalogram, EEG),52 despite the relatively high
cost of this drug. Future trials should clarify the benet
of this drug on impaired ambulation.
Bladder, bowel, and sexual dysfunction

Bladder dysfunction
About three-quarters of patients with MS have bladder
symptoms.53 The key CNS regions involved in the
regulation of micturition include the periaqueductal grey
matter, pontine micturition centre, medial frontal cortex,
hypothalamus, and sacral micturition centre.54 In MS,
bladder symptoms arise mainly from interruption of
connections between the pontine and sacral micturition
centres caused by spinal cord pathology.
General management
An initial assessment should establish whether urinary
symptoms are due to bladder ineciency (incomplete
emptying, residual urine, and frequency), bladder overactivity (urgency, frequency, and urge incontinence),
detrusor-sphincter dyssynergia (hesitancy, interrupted
stream, and incomplete emptying) or a combination of
two or more of these causes. We recommend that residual
bladder volume after micturition is measured and that
urinary tract infection is excluded before treatment is
considered. Urodynamics can aid assessment in more
complex situations.55
A uid intake of 12 L per day should be ensured. A
25% reduction in uid intake leads to improved
urgency, frequency, and nocturia in patients with
bladder overactivity.56 Pelvic oor exercises, perhaps
with neuromuscular stimulation57 and regular bowel
emptying,55 should be considered. Finally, increased
intake of cranberry juice can be suggested because,
although not studied in MS, it reduces the recurrence
of urinary tract infection in healthy women58 and in
patients with spinal cord injury (in tablet form).59
For bladder ineciency (table 3), blockers can be
considered, although only one small randomised trial60
showed an improvement in urinary ow rate. However,
if the postmicturition residual volume is more than
100 mL, the treatment of choice remains clean intermittent self-catheterisation. If this is not sucient to
control symptoms, permanent catheterisation might
be advisable after urological consultation.
For bladder overactivity, results from a few small
studies of oral antimuscarinic drugs have shown
benecial outcome (table 3), although details on
randomisation and blinding were incomplete.63 Nevertheless, drugs such as oxybutynin are usually used as
rst-line treatment. Oxybutynin decreases bladder

emptying with consequent increased residual volume;
hence it is important to check the postmicturition
residual bladder volume before starting this treatment.
Increasing confusion can be seen in patients with
cognitive impairment, which is not surprising given the
anticholinergic eect of this drug. Therefore, we
recommend that this drug is used with caution in elderly
patients and those with pre-existing cognitive impairment. Tolterodine is a useful alternative, as a long-acting
preparation. Other drugs include trospium, propantheline, propiverine, and fesoterodine. Pair combinations
of oxybutynin, tolterodine, and trospium have been used
in patients with neurogenic detrusor dysfunction,
without inducing substantial side-eects.66 The most
recently tested antimuscarinic drugs showing benecial
eects are solifenacin and darifenacin, although they
have not been assessed in MS.79,80
Intranasal desmopressin spray is very useful for
nocturia. It reduces the number of voiding episodes and
increases the period of uninterrupted sleep,70,81 and it is
usually well tolerated. Hyponatraemia has been reported
in about 5% of cases.81 In a randomised placebocontrolled trial,71 cannabinoids reduced the number of
urge incontinence episodes in MS, based on patient
diaries. Results from a recent large randomised placebocontrolled trial82 showed little dierence in the number
of daily urinary incontinence episodes between the
group treated with an oromucosal spray containing
dronabinol and cannabidiol and the placebo group, but a
high proportion of secondary endpoints (including
patients perception of bladder symptom severity) were
in favour of the drug.
Intravesical injection of botulinum toxin A is an
eective treatment for symptoms of bladder overactivity, with benecial eects on incontinence episodes,
urinary leakage, reduced bladder capacity, maximum
detrusor pressure, and quality of life,6769 and is available
in major centres. The mean duration of eect is almost
10 months, after which the treatment can be repeated.69
However, not enough robust data on its ecacy and
safety exist, mainly because of the inconsistent use
of comparison interventions, and whether ecacy
increases with higher doses is unclear. The intravesical
vanilloid capsaicin and its analogue resiniferatoxin have
been shown to have benecial eects in small controlled
trials on incontinence frequency and bladder capacity
in patients with MS.72 Pelvic pain and ushing are
frequent side-eects, and these drugs are not given
regularly to patients with the disorder.
Surgical treatments
Sacral neuromodulation with electrical stimulation of
the S3-nerve root can be considered in detrusor
overactivity unresponsive to botulinum toxin, especially
in milder forms of MS.55 This treatment inhibits the
micturition reex. Although the total number of patients
1187
Review
Study design
Main results
Randomised placebo-controlled trial; 18 patients
Flow rates, residual volumes
Mean 41% improvement in peak ow rate
Dasgupta et al61
Open-label study; 36 patients (29 with MS); mean follow-up

115 months
Flow rates, residual volumes; patient

questionnaires
Symptom improvement in 70% of patients; mean residual

volume reduced from 175 mL to 68 mL
Prasad et al62
Randomised controlled crossover study; 28 patients with MS Residual volumes, patient

questionnaires
Signicant eect of vibration on residual volumes but not

incontinence episodes or micturition frequency
Nicholas et al63
Cochrane review (3 of 33 trials selected as suitable)
Bladder volumes, urological symptoms
Evidence too weak to advocate use of antimusarinics
Gajewski and Awad64
Randomised prospective study of oxybutynin vs

propantheline; 34 patients with MS
Urological symptoms, urodynamics
Oxybutynin superior to propantheline
Fader et al65
Randomised double-blind crossover trial of intravesical

atropine vs oral oxybutynin; 64 patients with MS
Bladder capacity, urological symptoms
Intravesical atropine at least as eective as oxybutynin with

fewer side-eects
Amend et al66
Randomised unblinded comparative study of combination

dual therapy (two of oxybutynin, tolterodine, trospium);
27 patients (2 with MS)
Urodynamics, urological symptoms
Benecial eects of dual therapy without signicant

side-eects
Urodynamics,urological symptoms
Most studies reported superiority to placebo; overall, they

showed promise for therapy of overactive bladder; optimum
dose not known
Bladder ineciency
Indoramin (1 blocker)
ORiordan et al60
Vibrating device
Bladder overactivity
Antimuscarinics
Intravesical botulinum toxin A

Duthie et al67
Cochrane review (8 randomised studies included);

participants had neurogenic, overactive bladders
Ehren et al68
Randomised placebo-controlled double-blind trial; 31 patients Cystometry, quality of life

with neurogenic detrusor overactivity (6 with MS)
Signicant benets of one dose of botulinum toxin on

cystometry and quality of life
Kalsi et al69
Open-label study; 43 patients with MS and detrusor

overactivity
Cystometry, urological symptoms
Signicant improvements on outcome measures;

98% needed self-catheterisation
Meta-analysis from 1990 to 2003 (5 randomised

double-blind placebo-controlled crossover trials);
115 patients with MS and urinary symptoms
Urinary frequency and volume; patient

questionnaire
Moderate reduction in voiding frequency; large eect on

urine volume 6 h after dose but small eect 24 h after dose;
serum sodium and osmolality not signicantly aected
Part of CAMS study3 (630 patients with MS); three arms: oral
cannabis extract, dronabinol, and placebo
Incontinence diaries
All three groups showed signicant benet: oral cannabis

38%, dronabinol 33%, placebo 18%; both active treatments
showed signicant eects over placebo
Systematic review; 10 randomised trials of 288 patients

(43% with spinal cord injury; 52% with MS); capsaicin,
6 trials; resiniferatoxin, 4 trials; botox, 2 trials
Incontinence diaries
Capsaicin superior to placebo; resiniferatoxin similar to

capsaicin
Desmopressin
Bosma et al70
Cannabinoids
Freeman et al71
Intravesical vanilloids
MacDonald et al72
Peripheral nerve stimulation

Fjorback et al73
Open-label study of acute posterior tibial nerve stimulation;

8 patients with MS
Cystometry
No acute eect of posterior tibial nerve stimulation on

bladder contractions
Kabay et al74
Open-label study; 12 weeks of posterior tibial nerve

stimulation; 19 patients with MS
Urodynamic studies
Signicant improvements in cystometric capacity, ow rate,

and detrusor pressure with stimulation
Sacral nerve neuromodulation

Wallace et al75
Retrospective case series of 28 neurological patients (13 with Urological diaries

MS) with urinary dysfunction
Large improvements in urological measures after

implantation
Fowler et al76
Double-blind randomised placebo-controlled trial; 217 men

with MS and erectile dysfunction; 12-week duration
Patient questionnaires (international

index of erectile function, global
ecacy, quality of life)
Very signicant benets with sildenaleg, 89% of patients

treated with sildenal reported improved erections
compared with 24% treated with placebo
Safarinejad77
Double-blind randomised placebo-controlled study;

203 men with MS and erectile dysfunction; 24 doses given
International index of erectile function

questionnaire; sexual encounter prole
diary
Small but signicant eects; improved erections reported by

33% of patients given sildenal and 18% of patients given
placebo (p=004)
Dasgupta et al78
Double-blind randomised placebo-controlled crossover trial;

19 women with MS and sexual dysfunction
Validated questionnaires; pudendal and

tibial evoked potentials
Signicant improvement only in lubrication domain of sexual

function with sildenal; no improvement in quality of life
Sexual dysfunction
Sildenal
recent trials. MS=multiple sclerosis.
Table 3: Selected studies or reviews of treatments for bladder ineciency and overactivity and sexual dysfunction in MS
1188
Review
studied is low, results are very encouraging in terms of

improvement in bladder symptoms and urodynamic
parameters.75 Other surgical procedures, such as urinary
diversion or bladder augmentation, can be oered to
patients with intractable urge incontinence or irreversible complications from long-term catheters.55
Peripheral nerve stimulation of the dorsal penile or
clitoral nerves73 and posterior tibial nerve74 can be eective
in suppression of detrusor contractions in MS, but
conrmation from larger trials is awaited.
Bowel dysfunction
Bowel dysfunction manifesting as constipation or faecal
incontinence, despite being present in more than 50% of
patients with MS, is poorly studied compared with
bladder dysfunction.83 General management includes
dietary and mobility advice and review of drug sideeects and concurrent medical problems (eg, obstetric
injury).84 Pharmacological and other therapies can then
be considered.
Constipation
Although increasing uid and bre intake is advised for
constipation, few studies have focused specically on
patients with MS.85 Similarly, bulking drugs (which
increase faecal mass and stimulate peristalsis), stool
softeners, osmotic laxatives (which increase uid
retention within the bowel; eg, lactulose), and stimulant
laxatives (eg, senna and bisacodyl) are often recommended, although no specic evidence exists for their
ecacy in MS. As they increase intestinal motility
without causing incontinence,86 they are often the rstline treatments.
Rectal stimulants (such as glycerol and bisacodyl
suppositories)87 can be used to manage the timing of
defecation. Behavioural feedback is eective for treatment of constipation or faecal incontinence in
some patients with MS, especially if they are mildly
to moderately disabled.88 This treatment improves
spontaneous bowel-emptying frequency and reduces
abdominal pain, bloating, and the concomitant use of
oral laxatives in patients with idiopathic chronic constipation.89 If these measures fail, surgical intervention
(such as colostomy or ileostomy) can be considered,
usually in severe cases. Transanal colonic irrigation has
also been studied with benecial results in patients with
spinal cord injury and other neurological diseases.90
Faecal incontinence
Faecal incontinence is a very dicult symptom to
manage. Although no evidence base exists for their use
in MS, antimotility agents (such as codeine phosphate
and loperamide) and rectal stimulants represent the
main treatments, because they help to regulate discharge
and reduce the frequency of incontinence episodes.
Rectal stimulants are favoured when timing of defecation
needs to be planned. Biofeedback has also been reported
to be eective.88 End stoma, dynamic graciloplasty,

articial bowel sphincter,91 sphincter repair, and sacral
nerve stimulation92 (in cases of structural anal sphincter
damage) are surgical treatments for faecal incontinence
but have not been investigated in MS.
Sexual dysfunction
The main complaints in male patients with MS are reduced
libido, erectile impotence, and premature ejaculation; 84%
of 31 men with MS had one of these symptoms in one
study,93 with a signicant eect on quality of life. For
women, research interest in this area has grown, both for
diagnosis and treatment. The main complaints in female
patients with MS are reduced libido, diculties in
achieving orgasm, and decreased vaginal lubrication;
85% of 78 women with MS had one of these symptoms,
aecting their quality of life.93 Sexual dysfunction is less
frequent in newly diagnosed female patients with low
disability than in women at a later stage of the disease.
Table 3 shows treatments for sexual dysfunction that
have been studied or reviewed in MS. For men, sildenal
was the rst phosphodiesterase-5 (PDE5) inhibitor to be
tested in this disease. It enhances the erectile response
through the inhibition of the breakdown of cyclic
guanosine monophosphate (cGMP). Positive results
were reported in two double-blind randomised placebocontrolled trials in patients with MS (erections improved
in 89%76 and 33%77 of patients treated with sildenal
compared with 24%76 and 18%77 of patients on placebo).
However, in both trials, the patients studied had
relatively low levels of disability, which suggests mild
spinal cord involvement, and were young, which makes
extrapolation dicult to older patients with more severe
disease. An eect of unblinding might also have been
present, because adverse eects for sildenal were more
frequent than for placebo. However, the drug was
generally well tolerated. Encouraging results have
recently been shown for other PDE5 inhibitors, such
tadalal and vardenal, in several disorders other than
MS. Only one open-label study94 showed a possible
benet for tadalal in MS. Sublingual apomorphine can
be used as an alternative to sildenal,53 although no
evidence of its ecacy in MS has been described.
Alprostadil (prostaglandin E1) can be given as
intracorporeal injection or transurethrally and has been
shown to be eective in a large sample of patients with
organic erectile dysfunction, without local adverse
eects such as priapism or brosis.95
In women, results from a small but well designed
study assessing sildenal78 showed poor benet.
Generally, denitive evidence to support its routine use
remains weak96 because trials have included small
sample sizes, inappropriate statistical tests, and
assessment techniques that are not validated. Androgen
hormone therapy (methyltestosterone) in combination
with oestrogen can be helpful,53 although specic trials
in MS have not been done.
1189
Review
Fatigue, cognitive impairment, and mood

disturbance
Fatigue
Fatigue is a complex symptom that dees denition and
measurement. Patients complain of dierent types of
fatigue, such as relapse-related fatigue, excessive tiredness
after exercise, and excessive daytime sleepiness. It is
present in up to 74% of patients with MS97 and is often
described as their most disabling symptom.
General measures
The patients daily routine should be reviewed and
activities rearranged to minimise the eect of fatigue. The
sleep pattern should also be reviewed to consider, for
example, whether nocturnal spasms or nocturia contribute
to poor sleep. Mood should be assessed to establish
coexistent depression. Other conditions should be
considered, such as anaemia or hypothyroidism. The
patient should maintain a healthy diet and regular physical
activity.98 Pharmacological treatments can be considered
when fatigue remains a disabling symptom despite the
introduction of fatigue management programmes, which
attempt to minimise the eect of this symptom on daily
activities, and the provision of advice on work simplication
techniques. Alternative medicines and cooling therapy99
have captured interest but not enough scientic evidence
exists to support their use.
Drug treatment has not been very successful in alleviating
fatigue (table 4). Amantadine has been studied,101103 but
deciencies in clinical trial design limit the interpretation
Action
Daily dose
(minmax)
Amantadine
200600 mg
Cholinergic,
dopaminergic, adrenergic,
and glutamatergic eects
on the CNS
Numerous side-eects: anorexia, nausea,

insomnia, visual hallucinations, blurred
vision, gastrointestinal symptoms, livedo
reticularis, peripheral oedema, dry mouth,
urinary retention
Modanil
Amphetamine-type
action
100400 mg
Dose-dependent side-eects: restlessness,

loss of appetite, insomnia, nervousness,
dizziness, headache, nausea, asthenia
Pemoline
Stimulant of the CNS
2060 mg
Insomnia, irritability, anorexia, weight loss,

tremor, tachycardia, increased risk of seizures
Aminopyridine
Blocks potassium
channels, resulting in
improved conduction;
possible modulator of
brain activity100
560 mg
Dizziness, insomnia, paraesthesias, asthenia,

nausea, headache, tremor, light-headedness,
epileptic seizures (with doses of 30 or 35 mg
twice a day), anxiety
Carnitine
Cellular component with

a role in cellular
metabolism
16 g
Insomnia, nervousness, gastrointestinal

symptoms
DMTs
Side-eects vary depending on specic DMT

Possible eect on fatigue Standard
doses of
via the drugs antiinammatory mechanism specic DMTs
The information given on action, dose, and side-eects is based on all the articles read for the preparation of this
Review, on the drug leaets, and on the authors own experience. DMTs=disease-modifying treatments.
Table 4: Drugs used for treatment of fatigue in MS
1190
of the results. Despite preliminary and encouraging

results obtained with open-label104 and single-blind105
studies, modanil was ineective for treatment of fatigue
in 115 patients at doses ranging from 100 to 400 mg
per day.106 However, results from a randomised doubleblind trial107 suggested that modanil 200 mg per day
could improve fatigue, concentration, and upper limb
function, although the sample size was small. Pemoline
has been reported to be ineective103 and poorly
tolerated.108 Small positive eects on fatigue, although
subjective, have been described for aminopyridines.48,109,110
A possible eect of levocarnitine on fatigue has been
shown in patients treated with disease-modifying drugs,111
and increased benet compared with amantadine has
been reported,112 although this evidence is preliminary
because of the small sample size (n=36) of this study. An
improvement in self-reported fatigue has been described
in association with disease-modifying treatments,
including glatiramer acetate97,113 and natalizumab,114 but
the results need conrmation in more focused,
randomised, double-blind trials.
Cognitive dysfunction
Cognitive impairment is common (4070%) in patients
with MS115 and occurs in all phenotypes.116 Several cognitive
domains, especially memory, speed of information
processing, mental exibility, and executive functions, are
aected. Further methodologically sound research needs
to be done before dierent cognitive rehabilitative
interventions can be recommended in MS.117 Very few
studies have examined the eect of disease-modifying
drugs with cognition as the primary outcome (table 5).
Incomplete evidence exists that interferon beta-1b and
interferon beta-1a might improve or stabilise cognitive
scores on various assessments, including the Wechsler
memory scale visual reproduction-delayed recall test,128
the Wisconsin card sorting test129 for frontal lobe function,
and more comprehensive neuropsychological batteries.118
Results from a recent large observational study in patients
with MS treated with interferon beta-1a showed a
32% lower risk of cognitive impairment with high doses
of interferon than with low doses, but these results might
have been confounded by the low-dose group having
greater cognitive impairment at baseline than the highdose group.119 Additionally, the mechanisms of action are
speculative.
Large, double-blind randomised placebo-controlled
clinical trials in MS are needed to clarify whether
acetylcholinesterase inhibitors have an eect on cognition
in this disorder. A possible benecial eect for donepezil
on memory function and cognition has been reported120,121
with tolerable side-eects, which included abnormal
dreams, in patients with MS who had impaired verbal
memory. However, this trial did not include patients with
a mini-mental state examination score lower than 26,
clinical depression, or severe disability, and the two
groups were not balanced for phenotype, sex, and
Review
disability. Additionally, the treating physician also did the

assessment and, although the primary outcome favoured
donepezil, the eects were not signicant on an overall
composite cognitive score or on specic areas such as
word uency, spatial recall, or executive function. A
second larger study is currently underway.130 No signicant
dierences have been seen between rivastigmine and
placebo in terms of memory function.122
Memantine, an NMDA receptor, was tested in a
small, double-blind placebo-controlled trial that was
curtailed when nine of 19 patients with MS complained
of a deterioration in their neurological symptoms at
30 mg per day.123 These symptoms were reversed when
memantine was discontinued (table 5). Another larger,
placebo-controlled study compared memantine 10 mg
twice a day with placebo in 126 patients with MS and
showed no signicant treatment eect on cognitive
performance. Adverse events were infrequent and
mild, although fatigue and neurological eects were
Study design
more common with memantine than with placebo

(table 5).124
Studies of amantadine and pemoline125 and gingko biloba126
have shown disappointing results. In a double-blind
placebo-controlled randomised trial,127 L-amphetamine
sulfate was associated with improved learning and memory
and was well tolerated. However, in this large trial (n=151),
the primary outcomes were not signicant, although the
secondary outcomes did reach signicance. Additionally,
the duration of treatment was short (the maximum
treatment dose was maintained for 14 days), and changes in
mood during or after the trial were not examined, making
it impossible to ascertain the long-term eectiveness,
tolerability, and eect on mood of the drug.
Psychiatric and psychological dysfunction

Psychiatric disorders such as major depression, bipolar
disorder, pseudobulbar aect, and psychosis are known
to have a higher prevalence in patients with MS compared
Main results
Interferon beta-1a
Fischer et al118
Randomised placebo-controlled study; 161 patients Comprehensive neuropsychological battery

with relapsing remitting MS; 2-year duration
Patti et al119
Observational 3-year study of 459 patients with

relapsing remitting MS naive to treatment;
318 patients followed up
Signicant benet of active treatment on information

processing and learning/memory; benecial trend for
visuospatial ability and problem solving
Raos brief repeatable battery; Stroop colour-word task;

Hamilton depression rating scale; quality of life
questionnaires; conventional MRI
32% lower risk of cognitive impairment with high dose

(44 g) than with low dose (22 g; p=001), but baseline
cognitive impairment was higher in low-dose group
Acetylcholinesterase inhibitors
Krupp et al120 and
Christodoulou et al121
Double-blind placebo-controlled randomised study

of donepezil; 69 patients with MS and cognitive
impairment
Selective reminding test (verbal learning and memory)
Signicant improvement in memory performance with

treatment (66% of patients treated with donepezil vs
32% on placebo); abnormal dreams reported as a
side-eect of donepezil
Shaygannejad et al122
Double-blind placebo-controlled randomised study

of rivastigmine; 60 patients with MS and cognitive
impairment
Wechsler memory scale
Slight but signicant memory improvement in both

groups; no dierences between rivastigmine and
placebo
Villoslada et al123
Double-blind placebo-controlled randomised

crossover study; 19 patients with MS and cognitive
impairment
Brief repeatable battery
Trial stopped after neurological worsening in 9 patients

(eg, with blurred vision, fatigue, headache, muscle
weakness, walking diculties); eects reversed after
treatment was stopped
Lovera et al124
Double-blind placebo-controlled randomised study; Paced auditory serial addition test; California verbal
learning test-II; long delay free recall test
126 patients with MS and cognitive impairment;
4-week titration then 12-week maintenance period
Memantine
No dierence for cognitive eects; patients given

memantine had more fatigue (6 vs 4, not signicant)
and neurological side-eects (17of 58 vs 6 of 58;
p=0003), including anxiety, confusion, dizziness,
spasticity, and somnolence
Amantadine and pemoline

Geisler et al125
Placebo-controlled randomised study of

amantadine, pemoline, and placebo; 45 patients
with MS and severe fatigue
Neuropsychological tests of multiple domains (attention, Signicant improvements on neuropsychological tests

verbal and non-verbal memory, motor speed)
for all three arms; no dierences between amantadine,
pemoline, and placebo
Gingko biloba
Lovera et al126
Double-blind placebo-controlled randomised study; Several neuropsychological tests including California

38 patients with MS and cognitive impairment
verbal learning test-II, paced auditory serial addition test
Overall, no signicant improvement in cognitive

function
L-amphetamine sulfate
Morrow et al127
Double-blind placebo-controlled randomised study; Subject global assessment of change; single-digit

151 patients with MS and cognitive impairment
modalities test
No signicant dierences in main outcomes; some

benets for secondary outcomes testing learning and
memory; ndings need replication
recent trials. MS=multiple sclerosis.
Table 5: Selected studies and reviews of treatment of cognitive dysfunction in MS
1191
Review
with the normal population.131133 Importantly, depression

can exacerbate cognitive dysfunction in MS.134 Overall, not
enough well designed and scientically sound trials of
pharmacotherapy or psychotherapy in MS exist, and,
therefore, management of these disorders follows the
recommendations of general psychiatry. Several therapeutic trials in depression have specically recruited
patients with MS. Cognitive behavioural therapy has been
reported to be helpful,135 as well as uoxetine,136 sertraline,137
and moclobemide,138 a reversible monoamine oxidase A
inhibitor, all with good tolerability.
For pseudobulbar aect or involuntary emotional
depression disorder, dextromethorphan with quinidine
(DMq) has been shown to have a benecial eect on the
number of episodes of laughing and crying and quality of
life in patients with MS in two studies.139,140 In the rst
study,139 a randomised controlled trial of 150 patients, a
relatively high dropout rate was noted (2729%), but the
sensitivity analyses showed that the assessment of
ecacy was not biased.139 In the second study,140 a
randomised double-blind trial comparing placebo with
DMq at 30/10 mg and 20/10 mg, 283 of 326 patients
(87%) completed the trial.140 The frequency of episodes of
pseudobulbar aect was 469% (p<00001) lower
for DMq 30/10 mg and 490% (p <00001) lower for DMq
20/10 mg than for placebo. Results from a double-blind
crossover study141 comparing amitriptyline with placebo
in patients with MS with pathological laughing and
weeping showed a benecial eect of this medication,
although the number of patients (n=12) was too small to
draw a denitive conclusion.
Pain
Pain occurs frequently in patients with MS, even in the
early stages,142 and is often severe. Many studies have
examined the epidemiology of pain in this disorder and
have reported a prevalence ranging from 30%143 to 90%.144
Pain in these patients can have either neurogenic or nonneurogenic causes, or a combination of both. Neurogenic
pain includes paroxysmal pain (trigeminal neuralgia,
painful tonic spasms, and Lhermittes phenomenon),
persistent pain (burning dysaesthesia of the limbs and
trunk), and other forms of neurogenic pain, such as
migraine with and without aura and tension-type
headache, which seem to be more prevalent in patients
with MS than in the general population.145 Non-neurogenic
pain generally originates from musculoskeletal or soft
tissue abnormalities, and relates to paralysis, immobility,
or spasticity. In this Review, we will deal with paroxysmal
and persistent forms of neurogenic pain. Treatment
recommendations tend to be derived from research in
disorders other than MS because randomised controlled
trials in MS are rare.
Paroxysmal pain
Trigeminal neuralgia (table 6) has a higher prevalence in
people with MS than in the general population.165
1192
Recommendations for pain management have been

reviewed166 and include carbamazepine or oxcarbazepine
as rst-line treatments, and microvascular decompression
or radiofrequency treatment of the Gasserian ganglion
as surgical procedures. Lamotrigine,147 gabapentin,148
topiramate,149 and misoprostol150 have been studied in
MS with benecial eects, although the studies were
small and uncontrolled. Larger controlled studies,
including head-to-head trials against established drugs
such as carbamazepine, are needed to establish the
ecacy of these second-line drugs in patients with MS.
Surgical treatments for patients unresponsive to
pharmacological treatment are less eective in this
disorder than in idiopathic trigeminal neuralgia.151 Of
these, gamma-knife radiosurgery has been reported to
control pain eectively in 54% of 37 patients with MS
and trigeminal neuralgia for up to 5 years.152 Painful
tonic spasms can be treated with gabapentin,167
tiagabine,168 and botulinum toxin A,169 although these
drugs have been tested only in an open-label setting.
Lhermittes sign is treated with general antiepileptic
drugs, despite the small amount of evidence. Sodiumchannel blockers (such as lidocaine and mexilitene)
could be helpful for painful tonic spasms and Lhermittes
sign, as shown by a small open-label study in patients
with MS.170
Persistent pain
Management recommendations for neuropathic pain
in MS are similar to those for general causes of
neuropathic pain,171 mainly because trials in patients
with this disorder are scarce (table 6). Recent guidelines
from the UK National Institute for Health and Clinical
Excellence suggest that treatment should start with
amitriptyline or pregabalin for neuropathic pain.172 In
MS, results from small open-label studies have shown
benecial eects for gabapentin153 and lamotrigine.154
However, the results of a randomised double-blind
placebo-controlled crossover pilot study155 did not show
a benecial eect for lamotrigine on central pain in
MS. Levetiracetam was studied in a small single-blind
randomised placebo-controlled trial,156 with some
benet reported.
Cannabinoids are of particular interest. Although
there were no denitive benets on spasticity in the
studies described earlier in this Review, patient-reported
pain signicantly improved.3 A meta-analysis157 showed
that cannabinoid-based drugs (including dronabinol,
Sativex, and cannabidiol) are helpful for treatment of
neuropathic pain in MS, despite the small number of
trials and patients treated. The results of a randomised
double-blind placebo-controlled crossover study158 of
dronabinol showed a signicant, albeit modest,
analgesic eect on central pain in MS.158 Limitations of
this study included the absence of statistical correction
for multiple comparisons and treatment length of only
3 weeks. Additionally, since only patients with sensory
Review
abnormalities at the maximum pain site were included,

whether other types of central pain such as those related
to spasms might benet from the same drug remains
unknown. An oromucosal spray that contains equal
amounts of dronabinol and cannabidiol (Sativex) has
provided encouraging results in one study.159 Another
study reported negative results11 but used dierent
doses and outcome measures and the two reports are
therefore not comparable. Pain reduction was
maintained during 2 years of treatment, without
induction of tolerance, and with only mild to moderate
side-eects in a further study.160 Finally, nabilone, a
synthetic cannabinoid, was eective in reducing
otherwise uncontrollable pain, but not spasticity, in a
double-blind placebo-controlled trial of spasticity-
related pain in MS.161 This study lasted for only 9 weeks

and only 11 of the 13 patients completed it; one of the
dropouts was attributable to an exacerbation of
weakness in the lower limbs, possibly due to nabilone.
The evidence for non-pharmacological treatments in
patients with MS with neuropathic pain is weak and is
based on small open-label trials and case-reports.
Therefore, when pharmacological relief of neuropathic
pain is insucient, recent guidelines173 from the
European Federation of Neurological Societies (EFNS)
on neurostimulation therapy for neuropathic pain can
be followed.
In MS specically, intrathecal infusions of baclofen
and morphine, or both,27 might be benecial in severe
cases. Transcutaneous electrical nerve stimulation
Study design
Main results
Observational study of 35 patients with MS and TN;

27 treated with carbamazepine
Pain scores and symptoms
10 of 27 patients had complete pain relief; 10 of 27 patients had

partial relief; 4 of 27 patients stopped because of side-eects
Small open-label study; 5 patients with MS and TN
All 5 patients with MS had symptomatic relief
Small open-label study; 11 patients with MS and TN

intolerant or refractory to carbamazepine or
lamotrigine
Good pain control in all but one patient when given gabapentin
combined with lowered doses of carbamazepine or lamotrigine
Small open-label study; 6 patients with MS and

refractory TN
Complete resolution of pain in all 6 patients; one patient needed

topiramate with carbamazepine to maintain relief
Small open-label study; 18 patients with MS and

refractory TN
14 of 18 had a more than 50% reduction in attack frequency and

intensity
Observational study; 35 patients with MS and

medically intractable TN
Imaging and operative ndings; pain

scores and symptoms
Neurovascular compression found in 46% of patients; long-term

outcome excellent in 39% and poor in 39% of patients; overall
results less satisfactory than for idiopathic TN
Observational study; 37 patients with MS and TN
Reasonable pain control in 83% of patients at 1 year and 54% at

5 years; 40% of patients had a second procedure for ongoing pain
Open-label study; 25 patients with MS and

neuropathic pain
Excellent to moderate pain relief in 15 patients
Cianchetti et al154
Open-label study; 21 patients with MS and burning

paraesthesias, paroxysmal or continuous limb pain,
and painful tonic spasms; lamotrigine used as
adjunct
8 of 9 patients had improvements in burning paraesthesia; 1 of

6 patients had improvements in continuous limb pain; 5 of
8 patients had improvements in painful tonic spasms
Breuer et al155
Double-blind randomised placebo-controlled

crossover trial; 12 patients with MS and central
neuropathic pain
Brief pain inventory, neuropathic pain

scale, quality of life questionnaire
No signicant dierences between lamotrigine and placebo
Single-blind randomised placebo-controlled trial;

20 patients with MS and central neuropathic pain
Visual analogue pain scale, expanded

disability status scale, Hamilton
depression scale, quality of life
questionnaire
Signicant benet of levetiracetam for all study outcomes
Trigeminal neuralgia
Carbamazepine
Hooge and Redekop146
Lamotrigine
Lunardi et al147
Gabapentin
Solaro et al148
Topiramate
Zvartau-Hind et al149
Misoprostol
DMKG Study Group150
Microvascular decompression
Broggi et al151
Gamma-knife radiosurgery
Zorro et al152
Persistent neurogenic pain

Gabapentin
Houtchens et al153
Lamotrigine
Levetiracetam
Rossi et al156
(Continued on next page)
1193
Review
Study design
Main results
(Continued from previous page)

Cannabinoids
Zajicek et al3
Randomised placebo-controlled trial of oral cannabis Ashworth spasticity scale; pain-related

scale
extract and dronabinol; 630 patients with MS and
spasticity
No improvement on spasticity scale but improvements in

patient-reported spasticity and pain
Iskedjian et al157
Meta-analysis; 7 studies of central neuropathic pain

syndromes including MS; randomised placebocontrolled blinded designs; 298 patients pooled
Pain-related scales
Pain signicantly better with cannabinoid (Sativex, cannabidiol,

dronabinol) treatment (p<0001)
Svendsen et al158
Randomised double-blind placebo-controlled

crossover trial of dronabinol; 24 patients with MS
and central pain
Pain-related scales
Median spontaneous pain intensity lower in the treatment group

(p=002); dierence between treatments in pain reduction from
baseline was around 21%
Rog et al159

parallel trial of Sativex; 64 patients with MS and
central pain
Pain and sleep disturbance scale (11-point Signicant improvements in pain and sleep disturbance with
numerical rating scale)
active treatment
Rog et al160
Uncontrolled open-label extension of Rog et al159

study of Sativex; 63 patients with MS and central
pain
Pain and sleep disturbance scale (11-point Pain reduction maintained with no tolerance; 92% of patients had
numerical rating scale); adverse eects
side-eects (mostly mild or moderate)
Wade et al11

parallel group study of Sativex; 160 patients with
MS
Visual analogue scales for pain, spasticity,

spasms, bladder, tremor; multiple
functional and psychological rating scales
No dierence between active treatment and placebo groups for

pain, although improvement for both groups
Wissel et al161

crossover study of nabilone; 13 patients with central
pain (7 with MS)
Pain rating scale (11-point box test)
Signicant improvement in pain but not spasticity, motor

function, and activities of daily living in treatment group
TENS
Warke et al162
Randomised placebo-controlled study of 90 patients Pain rating scales; disability, mobility and
quality of life questionnaires
with MS and low-back pain; high vs low-frequency
TENS vs placebo
Chitsaz et al163
Randomised trial of TENS vs nortriptyline;

59 patients with MS and upper limb pain or sensory
symptoms
Pain rating scale
TENS equivalent to nortriptyline in reduction of upper limb pain

or sensory complaints
Retrospective analysis of 410 patients with pain

syndromes; 19 patients with MS
Pain rating scale; disability, depression,

and pain questionnaires
90% of patients with MS had initial pain relief; 80% had

long-term pain relief
No signicant eects after correction for multiple comparisons
Spinal cord stimulation

Kumar et al164
recent trials. Sativex is an oromucosal spray containing dronabinol and cannabidiol. MS=multiple sclerosis. TENS=trancutaneous electrical nerve stimulation. TN=trigeminal neuralgia.
Table 6: Selected studies and reviews of treatment of trigeminal neuralgia and persistent neurogenic pain in MS
(TENS) might be benecial for chronic low-back pain.162

However, these ndings were not signicant when
corrected for multiple comparisons, and the patient
group was heterogeneous, including patients with
probable MS. Results from another randomised trial163
showed that the eect of TENS on pain and sensory
complaints in the upper limbs was similar to that of
nortriptyline163 in a small group of patients over a short
time period (8 weeks); however, no placebo group was
included in this study. Therefore, evidence for ecacy
of self-applied TENS remains poor. Spinal cord
stimulation can provide long-term pain relief in patients
with MS and low-back pain.164
Visual and brainstem symptoms

Visual dysfunction
Nystagmus results from the disruption of mechanisms
that control foveation. Management of nystagmus in MS
is challenging with a poor rate of treatment response.174
A few trials with small numbers of patients with MS
have been done. These trials focused on acquired
1194
pendular nystagmus, which includes quasi-sinusoidal

oscillations thought to result from deciencies in
feedback circuits between the brainstem and
cerebellum.175 Memantine (mainly an NMDA glutamate
antagonist) and gabapentin have both been eective in
treatment of acquired pendular nystagmus in
randomised, but small, studies that included patients
with MS.176,177 The most recent trial177 was a blinded,
crossover, therapeutic study of gabapentin (1200 mg
per day) versus memantine (40 mg per day) for acquired
nystagmus in ten patients, of which three had MS.177 The
heteregenous characteristics of nystagmus in such a
small group makes extrapolation of benets to the whole
population with MS dicult, but gabapentin can be
recommended as a rst-line treatment for nystagmus in
this disorder since it is well tolerated. Memantine has
been reported to cause deterioration of cognitive
symptoms in MS.123 Practically, it might be possible to
use memantine for nystagmus in this disorder, selecting
patients without signicant cognitive impairment and
cautiously titrating the dose. Further studies are ideally
Review
Search strategy and selection criteria

We searched PubMed for articles published from 1970 to
September, 2010, with the search term multiple sclerosis
combined with specic search terms that constituted the
subheadings (eg, spasticity, ataxia, bladder
dysfunction, fatigue). References from identied studies
were also checked and included if felt appropriate. Articles
published in English were considered. References from our
own les were also searched. More recent publications
(within the past 10 years) were preferentially selected,
although older references that were considered important
were also included.
warranted to clarify its safety prole. Second-line drugs

include clonazepam and antimuscarinics, although their
use might be limited by side-eects.174
Brainstem-related symptoms
Brainstem-related symptoms include dysphagia, speech
and respiratory dysfunction, and vertigo (if of central
origin), which are not uncommon in MS, especially in
more advanced cases. Management of mild dysphagia
and dysarthria requires the input and support of speech
and language therapy. More advanced cases of dysphagia
(eg, with frequent or severe choking) should be assessed
with videouoroscopy, which is used to establish function
of the anterior pharyngeal segment (ie, laryngeal
dysmotility) and posterior segment (ie, pharyngeal
constrictor dysmotility).178 If the aspiration risk is high
and food intake becomes insucient, then percutaneous
gastrostomy might be needed. For severe dysarthria,
communication aids might be useful.
Respiratory training can improve inspiratory179 and
expiratory180 muscle strength in patients with MS; however,
these studies were done in patients with mild to moderate
disability and, therefore, whether these interventions
might help patients with more severe disability and greater
respiratory impairment remains unknown. Additionally,
both studies recruited a low number of patients, the
treatment was short, and only one study179 included a
control group. Respiratory impairment seems to occur in
patients with MS even if they do not complain of specic
respiratory symptoms.181
Not enough evidence exists for treatment of vertigo in
MS. Measures generally recommended for patients with
vertigo also apply to patients with MS, who are most
commonly aected by benign positional paroxysmal
vertigo, followed by vertigo secondary to brainstem
involvement.182 Other brainstem-related symptoms include
paroxysmal phenomena such as painful spasms,
paroxysmal dysarthria,183 and dysarthria-ataxia syndrome,184
which are associated with demyelinating midbrain lesions.
In clinical practice, these syndromes seem to respond to
the antiepileptic drugs discussed for paroxysmal pain in
this Review.
Conclusions
A diverse and wide range of symptoms can occur in MS.
Optimum management requires a multidisciplinary
approach, and is focused on the needs of the patients and
their priorities. For most treatments, however, the
supporting evidence for their use in MS is weak and
often relies on evidence provided by other disciplines (eg,
general psychiatry, and urology). This restricted evidence
base is attributable not only to the paucity of trials done
so far and their methodological limitations, but also to
the diculty in assessing the eect of treatments in a
chronic condition such as MS, in which impaired
functions often interact (eg, impaired cognition, mood
disturbance, and fatigue). The key to the success of future
research into symptom management in MS must be
based on improved understanding of the underlying
pathological mechanisms and translation of this
knowledge into development of appropriate therapies.
Additionally, symptomatic treatments need to be assessed
rigorously in well designed trials in which clinical
outcome measures focus on symptoms and in which the
patient perspective is incorporated.14
Finally, the use of surrogate measures that focus on
underlying pathological processes should be considered
in future trials. For example, brain atrophy, which is a
marker of axonal loss, has been reported to predict
cognitive dysfunction in MS; therefore, neuroprotective
treatments could be tested to investigate whether they
induce cognitive improvement in patients with MS.
The development of more innovative therapies (eg,
cannabinoids for spasticity and donepezil for cognitive
function), better designed treatment trials (large randomised double-blind trials that are powered to detect the
desired eect), and use of patient-related outcome
measures (which must be t for purpose14) oer some
encouragement for the future. Further well designed
trials are needed before any new treatments can be
recommended in clinical practice. These trials need to
address practical issues, such as optimum length of
treatment, whether rebound eects or withdrawal eects
occur after a treatment is interrupted, the costeectiveness of new treatments, and the side-eect
prole in the long term.
Contributors
All authors contributed equally to the preparation of this Review. AJT
was involved in the conception, writing, critical reviewing, and revision
of the manuscript. OC and ATT were involved in writing, critical
reviewing, and revision of the manuscript.
Conicts of interest
AJT serves on advisory boards for Novartis and Eisai. He has received
honoraria and support for travel from Schering, Serono Symposia,
LaRoche, Novartis, and Teva. ATT and OC have no conicts of interest.
Acknowledgments
OC is a Wellcome Trust Clinical Advance Fellow. ATT is funded by the
Higher Education Funding Council for England. This work was done at
UCLH/UCL, which received a proportion of funding from the
Department of Healths National Institute for Health Research
Biomedical Research Centres funding scheme.
1195
Review
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Review

Pharmacological management of symptoms in multiple

issues that need to be addressed before starting treatment,

there aggravating factors? Urinary and bowel dysfunction,

been tested only in patients with spasticity after stroke.17

there is no need for electromyographic guidance. The

daily regimen. However, its eect disappears after

Most common side-eects

Main outcome measures

Binds the GABAB receptor,

Sedation, drowsiness, muscle

UK Tizanidine Trial5 Double-blind

Ashworth scale; activities of

Tizanidine reduces spasticity

Ashworth scale; knee-swing

Positive eect of tizanidine on

Ashworth scale; type and

Ashworth scale; Kurtzke

Signicant dierences on the

Modied Ashworth scale;

Ashworth scale; other

No dierence on the Ashworth

Probably interacts via

Signicant eect on spasticity on

Ashworth scale; visual

No dierence in spasticity on the

(Continues on next page)

www.thelancet.com/neurology Vol 9 December 2010

programme.31 A trend exists towards increased ecacy

Ataxia and tremor

address these disabling symptoms with scientically

Main outcome measures

Most common side-eects

(Continued from previous page)

Functional status (walking

No dierence between the two

Ashworth scale; muscle

All three drugs had a similar eect NA

Table 1: Selected studies and reviews of anti-spasticity drugs in MS

www.thelancet.com/neurology Vol 9 December 2010

studies of long-acting 4-aminopyridine (fampridine) have

standardised assessments of the timed 25-foot-walk test,50

Main outcome measures

Double-blind placebo-controlled crossover trial;

Self-rating scales, quantitative tremor

All patients improved on at least one outcome measure

Open-label study; 13 patients with MS and tremor

Patient assessment, blinded rating of

10 patients showed improvement

Double-blind placebo-controlled randomised crossover

Writing tasks, self-assessment, clinical

No eect for any treatment

Double-blind placebo-controlled randomised crossover

Writing tasks, self-assessment, nine-hole

12 of 16 patients with MS showed tremor reduction

Open-label prospective study; 14 patients with MS and

Writing tasks, self-assessment, nine-hole

Double-blind placebo-controlled randomised crossover

Nine-hole peg test, ataxia scores

Double-blind placebo-controlled randomised crossover

Tremor rating scale

Double-blind placebo-controlled randomised crossover

Fahns tremor rating scale A and B