Curr Neurol Neurosci Rep (2013) 13:320
DOI 10.1007/s11910-012-0320-5
DEMYELINATING DISORDERS (DN BOURDETTE AND V YADAV, SECTION EDITORS)
Pain and Multiple Sclerosis: Pathophysiology and Treatment
Claudio Solaro & Erika Trabucco &
Michele Messmer Uccelli
Published online: 19 December 2012
# Springer Science+Business Media New York 2012
Abstract Pain is a common symptom in multiple sclerosis
(MS) and has recently been estimated to be experienced by
up to 75 % of patients. Pain can be present at any point in
the course of the disease and patients may experience pain
from various causes simultaneously. Pain in MS can also be
secondary to other symptoms, such as spasticity, fatigue,
and mood disorder. Of all drug use to treat MS symptoms,
treatment for pain accounts for nearly 30 % of total use. At
the same time, patients report low satisfaction with pain
management. Pain affects quality of life and can influence
a persons participation in family life and work and affect
mood. Most of the pain literature in the field of MS is based
on open-label studies involving small numbers of subjects.
Placebo-controlled trials in severe pain syndromes such as
trigeminal neuralgia are unethical but for other types of MS-
related pain conditions, placebo-controlled trials are ethical
and necessary to establish efficacy, particularly given the
well-documented placebo effect for various painful condi-
tions This review discusses available data and emphasizes
areas of pain research that require further attention
Keywords Antiepileptic drugs . Baclofen . Cannabinoids .
Carbamazepine . Central pain . Gabapentin . Lamotrigine .
Levetiracetam . Multiple sclerosis . Neuropathic pain
treatment . Opioid analgesics . Painful tonic spasms . Pain
treatment . Pregabalin . Topiramate . Tricyclic
antidepressants . Trigeminal neuralgia treatment
This article is part of the Topical Collection on Demyelinating
Disorders
C. Solaro (*) : E. Trabucco
Head and Neck Department, Neurology Unit, ASL 3 Genovese,
Largo Rosso 3,
16153 Genoa, Italy
e-mail: csolaro@libero.it
M. Messmer Uccelli
Department of Research, Via Operai 40,
Genoa, Italy
Introduction
Multiple sclerosis (MS) is a chronic, demyelinating disease
of the central nervous system, with diagnosis occurring
typically between 20 and 40 years of age, although it can
be diagnosed in children and in older adults. MS is charac-
terized by various clinical courses, including a relapsing
remitting form which typically shifts to a progressive course
over time and a progressive form. Common symptoms
include, among others, sensory impairment, extremity
weakness, urinary dysfunction, visual impairment, fatigue,
spasticity, incoordination, and pain [1]. Pain may be the
most commonly treated symptom in MS, estimated to ac-
count for 30 % of all symptomatic treatment [2]. A number
of drugs are used for managing symptoms in MS, some of
which have been approved for the disease, whereas most
have been approved for other illnesses and have been found
to have some use in treatment of MS. There are no double-
blind, parallel-arm, placebo-controlled trials, and most ther-
apeutic approaches are based on clinical experience. Man-
agement of painful symptoms is important since pain has a
significant impact on patients quality of life.
Classification of Pain Syndromes
Pain is defined as an unpleasant sensory experience asso-
ciated with actual or potential tissue damage or described in
terms of such damage [3]. Treende et al. [4] classified pain
syndromes as nociceptive somatic/visceral and neuropathic
pain. Nociceptive pain occurs as an appropriate encoding of
noxious stimuli and represents a physiological response
transmitted to a conscious level when nociceptors in bone,
muscle, or any body tissue are activated, warning the organ-
ism of tissue damage, in turn eliciting coordinated reflexes
and behavioral responses. Neuropathic pain is typically
initiated by a primary lesion or dysfunction in the peripheral
or central nervous system, with no biological advantage
(such as warning), causing suffering and distress. Clinical
320, Page 2 of 9 Curr Neurol Neurosci Rep (2013) 13:320

hallmarks are burning, dysesthetic, piercing pain, painful
responses to nonpainful stimuli (allodynia), and/or in-
creased pain sensation when noxious stimuli are applied
(hyperalgesia) [4].
A 2008 report classified pain associated with MS in four
categories: continuous central neuropathic pain; intermittent
central neuropathic pain (i.e., trigeminal neuralgia, Lher-
mitte sign, glossopharyngeal neuralgia); musculoskeletal
pain (i.e., painful tonic spasms, pain secondary to spasticity,
pain related to being wheelchair-bound), and mixed neuro-
pathic and nonneuropathic pain (i.e., headache) [5].
Prevalence of Pain in MS
Previous estimates of the occurrence of pain in MS patients
ranged from 29 to 86 %, although these numbers have been
revised on the basis of several recent articles [627]; see
Table 1. Solaro et al. [18] reported, in a large epidemiolog-
ical study based on a face-to-face structured interview, that
43 % of MS patients experience at least one type of pain.
The presence of pain correlated with disability, disease
course, disease duration, and age but not with gender. In a
casecontrol study Svendsen et al. [17] evaluated 771 MS
patients using a postal questionnaire and found a high prev-
alence of pain in both MS patients and controls (79.4 % in
MS patients vs 74.7 % in controls), with no statistical
difference between subjects and controls, although pain in
MS patients was severer and more often interfered with
daily activities.
The remainder of the article will discuss the major cate-
gories of pain in MS, providing an overview of pathophys-
iology and treatment.

Table 1 Studies of the prevalence of pain in multiple sclerosis (MS)

Study N (men/women) Selection method Data collection Prevalence (%)

Clifford and Trotter [6] 317 (not available) Consecutive outpatients Chart review 29
Vermote et al. [7] 83 (not available) Rehabilitation inpatients McGill Pain 54
Questionnaire
Kassirer and 28, of whom 84 % Long-term outpatients Specific questionnaire 75
Osterberg [8] were wheelchair
users (26/2)
Moulin et al. [9] 159 (51/108) Outpatients Specific questionnaire 64
plus interview
Stenager et al. [10] 117 (52/65) Random sample of inpatients Specific questionnaire 65
Warnell [11] 364 (115/249) Outpatients Specific questionnaire 64
Archibald et al. [12] 85 (13/72) Outpatients Specific questionnaire 64
Indaco et al. [13] 141 (61/80) Outpatients Structured interview 57 (excluding headache)
Stenager et al. [14] 49 (22/27) Follow-up of younger Structured interview 86
individuals from a 1991
study
Beiske et al. [15] 142 (47/95) Outpatients Interview 73.9 (pain and/or
sensory complaints)
Ehde et al. [16] 442 (111/331) MS society member database Postal questionnaire 44
Svendsen et al. [17] 627 with MS Casecontrol study Postal questionnaire 79.4 (patients with MS
(214/413) vs vs 74.7 % in controls)
487 controls
Solaro et al. [18] 1,672 (520/1,152) Random sample of outpatients Structured interview 42.8
sterberg et al. [19] 364 (124/240) Single-center registry Postal questionnaire, 57.5
telephone interview,
in-person interview
plus examination
Ehde et al. [20] 180 (40/140) Study pool Postal questionnaire 66
Hadjimichael 9,115 (2,188/6,927) National patient registry Postal questionnaire 74.5
et al. [21]
Piwko et al. [22] 297 (68/229) Population-based Postal questionnaire 71
Khan and Pallant [23] 94 (26/68) Community-based Semistructured interview 67
Boneschi et al. [24] 428 (161/267) Outpatients Semi-structured interview 39.8
Douglas et al. [25] 219 (40/179) Community-based Structured interview 75
Hirsh et al. [26] 2,994 (390/2,604) MS population base Postal questionnaire 91
Seixas et al. [27] 85 (62/23) MS population base Interview 34
Curr Neurol Neurosci Rep (2013) 13:320
Continuous Central Neuropathic Pain
Pathophysiology
Although important advances have been made in changes
related to peripheral nervous system injury, the pathophys-
iological mechanisms of central neuropathic pain is poorly
defined. MS pain is thought to be a type of central pain
due to demyelinating lesions in areas involved in pain
perception.
Experimental autoimmune encephalomyelitis (EAE) is
an animal model of MS that is inducible in various rodent
strains by immunization with several myelin antigens, is
widely used in order to better understand the pathophysio-
logical features of the disease as well as the efficacy of
medication. However, there are few reports in the literature
specifically studying pain in EAE. The availability of an
animal model could be an important step for understanding
the mechanism underlying pain in MS and an opportunity to
test pharmacological therapies. Aicher et al. [28] used pro-
teolipid protein to induce active immunization (chronic-re-
lapsing form) and proteolipid-protein-specific splenocytes
for passive induction in SJL mice. Nociceptive testing was
done with withdrawal latencies to a radiant stimulus. In both
models, hypoalgesia peaked prior to the peak of motor
deficits, whereas during the chronic phase of the disease,
the mice developed hyperalgesia, thus suggesting that EAE
may be a useful model for pain. In a chronic-relapsing
model of EAE, Olechowski et al. [29] studied pain sensi-
tivity and found a significant decrease in elicited pain be-
havior. This behavior was found to involve the
glutamatergic system, suggesting a potential mechanism
underlying neuropathic pain. Thibault et al. [30] character-
ized sensory abnormalities including thermal and mechani-
cal hyperalgesia and showed a partial effect of medications
(gabapentin, duloxetine, and tramadol) in two EAE models.
Recently, it has been hypothesized that MS is an acquired
channelopathy [31]. Sodium channel Nav1.8, whose expres-
sion is normally restricted to the peripheral nervous system,
is present in cerebellar Purkinje cells in a mouse model of
MS. The ectopic expression of Nav1.8 contributes to symp-
tom development in the model. Dysregulated sodium chan-
nel expression on sensory fibers can lead to a functional
change in axonal conduction [32], contributing to neuro-
pathic pain. Although the theory is intriguing and several
hypotheses can be made regarding the mechanisms of action
of sodium channel blockers such as antiepileptic drugs (i.e.,
cerbamazepine) on pain in MS, no data are available to draw
definitive conclusions.
Although the field has gained insights into the patho-
physiological mechanisms of neuropathic pain, particularly
in animal models, their replication in human subjects is
unknown.
Page 3 of 9, 320
Prevalence of Central Neuropathic Pain
A number of studies have reported central neuropathic pain
to be among the commonest pain syndrome in MS, with a
prevalence of nearly 50 % [18]. The classic signs of central
pain such as hyperalgesia and allodynia have been reported
in 38 % of MS patients, although this frequency may seem
lower in clinical practice, perhaps in part due to the diffi-
culty of patients to describe pain [17]. Approximately 40 %
of patients describe a constant and burning sensation usually
involving the lower limbs, more frequently distally than
proximally. Thirty percent describe this pain as a deep or
muscular aching [15].
A recent study evaluated the location of lesions in MS
patients with or without chronic pain using brain and spinal
cord MRI. Thirteen MS patients with chronic pain and ten
MS patients without pain were evaluated. There was no
association between pain and the site of demyelination
(spinothalamic tract, dorsal columnmedial lemniscus, dor-
solateral funiculus, grey substance, thalamus, or capsula
interna) [33].
Treatment of Central Neuropathic Pain
The treatment includes tricyclic antidepressants, antiepilep-
tic medications, intrathecally administered baclofen, opioid
analgesics, anesthetic and antiarrhythmic agents, and
cannabinoids.
Tricyclic Antidepressants
Tricyclic antidepressants such as amitriptyline, nortriptyline,
and clomipramine have historically been considered first-
line drugs for treatment of central pain. They act at the
synaptic level, increasing serotoninergic and noradrenergic
transmission, as well as on sodium channels. Adverse
effects include drowsiness, dry mouth, constipation, urinary
retention, and hypotension, limiting their use in MS patients
[34]. There are no available recommendations as to optimal
dose scheduling.
Antiepileptic Medications
Antiepileptic medications are also used in treating central
neuropathic pain associated with MS. Solaro et al. [35]
evaluated the frequency of antiepileptic medication use
and reported adverse effects in a cohort of MS patients.
Carbamazepine is commonly used for treatment of neuro-
pathic pain in MS, although often with inadequate results
[35]. It has a significantly higher incidence of adverse
effects, with a high rate of discontinuation at relatively low
doses, as compared with gabapentin and lamotrigine. These
adverse effects include drowsiness, vertigo, hypertension,
320, Page 4 of 9
bradycardia, rash, neutropenia, and abnormal liver function
[36]. Discontinuation of carbamazepine, even at low doses,
is often necessary [35]. It was recently reported that patients
with MS and those with epilepsy have a similar occurrence
of cutaneous rash (17 % vs 13 %) when using carbamaze-
pine [37]. Cianchetti et al. [38] performed an open, add-on
study with 21 subjects with different types of neuropathic
pain, including 15 with central neuropathic pain. Lamotri-
gine was added to current pain therapy up to a dosage of
400 mg daily. In two of 15 individuals with MS treated with
a daily dose of 400 mg lamotrigine as an add-on therapy,
pain was successfully treated. Six of 15 patients reported
some improvement. Improvement was sustained from
4 months to 1 year. No relevant adverse effects were
reported. One randomized, double-blind, placebo-
controlled, cross-over study that included 12 patients with
MS reached a maximum lamotrigine dosage of 400 mg daily
and found no difference between the lamotrigine and place-
bo groups for the change in mean pain intensity [39]. Gaba-
pentin for treatment of pain was evaluated in an open-label
study of 25 patients with MS. Fifteen of 22 subjects reported
excellent to moderate relief of pain at a dosage of 600 mg
daily. Pain in 15 patients was either improved or resolved.
Adverse events occurred in 50 % of the study participants,
five of whom discontinued use of gabapentin because of
somnolence and dyspepsia [40]. A further case was reported
in which gabapentin at a dosage of 900 mg daily resulted in
dramatic improvement in dysesthetic limb pain, without no
adverse effects. Levetiracetam was used in 20 MS patients
with central neuropathic pain in a randomized, single-blind,
placebo-controlled study at a maximum dosage of 3,000 mg
daily. The 12 patients receiving active treatment reported a
significant reduction in pain compared with the placebo
group. Adverse events occurred in eight treated patients
versus five patients receiving placebo, with one individual
discontinuing treatment owing to somnolence [41]. A recent
double-blind, placebo-controlled study found no effect of
levetiracetam (3,000 mg/day, 6-week treatment periods) in
nonselected patients with central pain in MS, but an effect in
subgroups with specific pain symptoms was reported. There
were no differences in ratings of pain relief, total pain
intensity, or any other outcomes in the total sample (n0
27), but there was significant pain reduction, increased pain
relief, and/or more positive pain relief with levetiracetam
than with placebo in patients with intense pain or without
touch-evoked pain [42]. In one open-label pilot study of
pregabalin, an anticonvulsant agent, 16 subjects with MS
and paroxysmal pain reached a mean treatment dosage of
154 mg daily [43]. Pregabalin was effective in nine patients,
but three patients discontinued treatment owing to adverse
effects, specifically dizziness in one patient and general
malaise in two patients. A subsequent report on two patients
described delirium at a low dose of pregabalin (75 mg daily)
Curr Neurol Neurosci Rep (2013) 13:320
[44]. Both patients were older than 60 years and were
undergoing therapy with medication acting on the central
nervous system (benzodiazepine, baclofen, and/or trama-
dol). We suggest a careful evaluation of possible drug inter-
actions particularly in older patients when pregabalin is
prescribed.
Antiepileptic drugs appear to be at least partially effective
for treatment of central neuropathic pain associated with
MS, although with a lack of rigorous, MS-specific clinical
trials their full potential remains unknown.
Unfortunately, many patients never advance to the regi-
men necessary for pain relief because of intolerable adverse
effects [35, 36, 41].
Intrathecally Administered Baclofen
Two studies have looked at intrathecal medications for treat-
ing pain in MS. Four patients with spinal lesions experi-
enced markedly reduced central neuropathic pain with
50 g of baclofen delivered intrathecally [45]. Intrathecally
administered baclofen (51,200 g/day) and intrathecally
administered morphine (2109,500 g/day) reduced pain
in nine subjects with MS without serious adverse effects
[46]. Generally, support for the intrathecal administration of
baclofen in treating neuropathic pain in MS remains
insufficient.
Opioid Analgesics
Only one nonrandomized, single-blind, placebo-controlled
study of 14 subjects with MS-related central neuropathic
pain used intravenously administered morphine at a median
dose of 0.67 mg/kg body weight [47]. Four patients reported
that pain was reduced by more than 50 % after treatment.
Clearly, insufficient evidence exists for the use of morphine
for neuropathic pain in MS.
Cannabinoids
Cannabinoids, unlike most other drugs, have been rigorous-
ly assessed for the treatment of pain in MS. Four clinical
trials have been reported in the literature. In one trial, the
synthetic cannabinoid dronabinol improved pain at a daily
dose of 10 mg compared with placebo [48]. A second, 5-
week trial of an oromucosal spray form of the cannabis
extract 9-tetrahydrocannabinol (9-THC) reported benefit
with regard to pain intensity in the treatment group, al-
though treated patients experienced deficits in long-term
memory storage [49]. Sixty-three patients of the 64 who
completed the original randomized study continued in an
open-label extension trial for up to 2 years to determine
long-term tolerability and the effectiveness of 9-THC. In
28 patients who completed the 2-year follow-up, the mean
Curr Neurol Neurosci Rep (2013) 13:320
numerical rating score for pain in the last week of the
randomized trial was 2.9 (scale range 0.08.0) compared
with 3.8 in the placebo group. Ninety-two percent of the 63
patients experienced a least one adverse event. A third, 15-
week trial included 630 individuals with stable MS experi-
encing spasticity. Pain was assessed as a secondary out-
come, along with a number of other symptoms, using
subjective scales [50]. Although most patients in the treat-
ment arm reported improvement in pain, 20 % reported
worsening while receiving treatment with cannabinoids.
Finally, 9-THC and cannabidiol administered sublingually
were compared with a placebo in a consecutive series of
double-blind, randomized, placebo-controlled, single-
subject, crossover trials. The design consisted of 2-week
treatment phases and a subsequent double-blind phase of
6 weeks duration.
Although active treatment improved pain, as rated on a
visual analogue scale, the study findings were negative
owing to a large placebo effect [51].
There are more robust data for cannabinoids than for any
other drugs for treating neuropathic pain in MS, although no
head-to-head trial comparing them with other classic pain
treatments has been conducted.
Intermittent Central Neuropathic Pain
Trigeminal Neuralgia
Trigeminal neuralgia is likely the most widely recognized
neuropathic pain syndrome in MS. Prevalence ranges from
1.9 % to 6.3 % [18, 19, 52]. Trigeminal neuralgia is char-
acterized by paroxysmal, episodic facial pain, occurring in
the sensory trigeminal area, often triggered by external
stimuli [53]. A 2010 report, however, found no relationship
between trigeminal lesions and clinical symptoms, despite
extensive involvement of the entire trigeminal complex in
some cases [54]. The clinical features are the same as those
of the idiopathic form, with an absence of sensory loss and
the presence of trigger points, described by patients as an
electrical discharge. The first branch is rarely involved
alone, and there is involvement of the second and/or the
third branches in approximately 90 % of cases [55]. Atyp-
ical facial pain, often confused with trigeminal neuralgia, is
described as subcontinuous pain, with the absence of trigger
points and a general sensory deficit in the trigeminal nerve
area. In this type of pain the lesion is likely located along the
lemniscus lateralis pathway [56].
Pathophysiology of Trigeminal Neuralgia
Trigeminal neuralgia is likely due to an electric ectopic
discharge caused by a plaque at the trigeminal neuralgia
Page 5 of 9, 320
nerve entry zone in the pons. The presence of a plaque in
the proximal part of the trigeminal root was reported in an
MS patient who underwent a rhizotomy for treatment of
trigeminal neuralgia [57]. Mixed results have been reported
using MRI studies demonstrating multiple causes. A study
reported enhancement on T1-weighted images and hyperin-
tense lesions on T2-weighted images of the cisternal portion
of the nerve or at the root entry zone in eight of 275 scans,
although trigeminal neuralgia was not present [58]. In a
study of 74 Japanese subjects studied retrospectively, five
(6.8 %) showed a T1-hypointense and T2-hyperintense,
nonenhanced, linear lesion in the pons, in the intramedullary
portion of the nerve that was associated with different sen-
sory symptoms. Only one subject had trigeminal neuralgia
[59]. A further study of six MS patients with trigeminal
neuralgia demonstrated that all subjects had a plaque in the
pons, whereas no vascular compression was observed [60].
The role of neurovascular compromise in trigeminal neural-
gia has also been proposed. Meaney et al. [61] found a
plaque in the pons on MRI in one of seven patients, whereas
vascular compression of the nerve by an artery at the root
entry zone was demonstrated in five subjects. A further
study reported nerve compression in 23 of 35 cases (60 %)
[62], whereas T2-weighted imaging demonstrated a brain-
stem lesion in 26 of 35 subjects (74 %). Trigeminal evoked
potentials, infrequently used for MS patients with trigeminal
neuralgia, can help to indicate the site of lesions, as demon-
strated in two studies in which there were abnormal findings
for five of five patients and 11 of 13 patients [63, 64].
Treatment of Trigeminal Neuralgia
Although relatively uncommon in MS patients, trigeminal
neuralgia is extremely painful, with a relevant impact on
quality of life [52]. Treatment of trigeminal neuralgia pri-
marily consists of antiepileptic medications acting on
voltage-dependent sodium channels, such as carbamazepine
and lamotrigine. Although there have been no randomized
clinical trials, reports from small, open-label studies on
various medications are available: for cabamazepine [65],
lamotrogine [66], gabapentin [67], topiramate [68], combi-
nation therapy [69], and misoprostol [70]. Carbamazepine is
relatively effective in treating trigeminal neuralgia but may
result in adverse effects, particularly causing reversible
worsening of MS symptoms [35, 65]. Lamotrigine was
evaluated in three small studies, one involving lamotrigine
in combination with gabapentin [69, 71]. It was effective in
22 of 23 subjects when used individually and in five of five
subjects in combination with gabapentin [67, 72]. Gabapen-
tin was described in two small studies in a total of 13
subjects. Complete resolution of pain at low doses was
achieved in 11 of 13 subjects. Topiramate was assessed in
two small studies of eight subjects, of which seven reported
320, Page 6 of 9
resolution of pain at relatively low doses [68, 73]. Finally,
two studies of misoprostol, a prostaglandin E1 analogue,
demonstrated efficacy in nine of 25 subjects [70, 74].
In summary, there are insufficient data to make evidence-
based treatment decisions.
Surgical Interventions for Treatment of Trigeminal
Neuralgia
Glycerol injection [7577], radiofrequency lesioning [78],
and radiosurgery [79, 80] are procedures that ablate the
retrogasserian ganglion in order to interrupt the trigeminal
pathway. These procedures have been used in MS patients
with trigeminal neuralgia who have not responded to phar-
macological treatment. These procedures cause nerve dam-
age that may lead to adverse effects including hypoesthesia/
hyperesthesia, decreased corneal reflex, transitory mastica-
tory weakness, and hearing loss, although these effects are
uncommon. Microvascular decompression of the trigeminal
root may be effective in carefully selected subjects, although
recurrence of pain is relevant, suggesting that combined
mechanisms other than nerve compression have a role in
the generation of trigeminal neuralgia in MS [81].
A lack of long-term benefit and the occurrence of poten-
tially serious adverse effects dictates that surgical interven-
tions should be reserved for critical nonresponders to
medications.
Lhermitte Sign
Lhermitte sign is reported by 40 % of patients with MS, and
although it is quite common, it is not exclusive to the
disease. Lhermitte sign is described as a painful electric-
like sensation that runs down the back and into the limbs,
elicited by flexing the neck. Treatment with low doses of
carbamazepine is rarely requested by patients and is typi-
cally reserved for persistent cases [82].
Glossopharyngeal Neuralgia
Glossopharyngeal neuralgia is rare in MS. Pain is intense
and occurs in the posterior pharynx, tonsillar fossa, and base
of the tongue. One report on three individuals with MS
found a daily mean dose of 633 mg of carbamazepine to
be successful in reducing pain [83].
Musculoskeletal Pain
Painful Tonic Spasms
Painful tonic spasms occur in approximately 11 % of sub-
jects with MS and are described as cramping, pulling pain
Curr Neurol Neurosci Rep (2013) 13:320
that most commonly occurs in the lower extremities, rarely
in the upper limbs, more often at night, typically triggered
by sensory stimuli [18]. The origin of pain in painful tonic
spasms is due to ectopic impulses resulting from demyelin-
ation and axonal damage determining a painful sensation at
the level of the muscle [5].
Anecdotally, medications such as baclofen, benzodiaze-
pines, gabapentin, and carbamazepine are used for treating
painful tonic spasms. In an open-label study, gabapentin was
reported to be effective at a mean dosage of 487 mg daily in
22 of 24 individuals with MS who had painful tonic spasms,
of whom three experienced mild adverse effects [84]. In four
of seven patients, tiagabine, a selective inhibitor of the -
aminobutyric acid transporter, was effective in relieving
pain at a daily dose of 12.8 mg. Two subjects dropped out
of the open-label study owing to adverse events that includ-
ed drowsiness, dizziness, weakness, and nausea [85]. Final-
ly, in an open-label study in which subjects were evaluated
using polymyography, botulinum toxin was effective in
reducing painful tonic spasms in four of five individuals.
Treatment was maintained for at least 90 days, with no
adverse events reported [86]. In summary, although painful
tonic spasms have been successfully treated in some cases,
the small number of patients and the open-label design
prevent any conclusions as to the most effective treatment.
Pain Secondary to Spasticity
Pain in MS can be secondary to spasticity and successful
spasticity management reduces pain.
Pain Related to Being Wheelchair-Bound
Patients with a significant level of impairment may require
technical aids for mobility, and many may remain seated in a
wheelchair for extended periods of time. In these patients,
pain may be due to incorrect posture, improper use of
technical aids, and prolonged wheelchair use [87].
It is important that patients with mobility assistance
needs are evaluated for appropriate interventions. Pharma-
cological treatment should consist of anti-inflammatory
drugs or opioids, although specific studies in MS are not
currently available.
Conclusions and Future Directions
Recommendations for the treatment of pain in subjects with
MS based on rigorous scientific methods are unavailable
and so clinicians base treatment decisions on clinical expe-
rience [88]. The only medications studied in large clinical
trials are cannabinoids, although no head-to-head studies
with other medications for pain associated with MS are
Curr Neurol Neurosci Rep (2013) 13:320
currently available. Data suggest that cannabinoids may
be useful for treating pain in MS, although the safety
profile remains a matter of discussion [89]. Only five
randomized clinical trials on central neuropathic pain
are available in the literature but the sample sizes were
small [39, 41, 42, 48, 49], and no head-to-head trials
have been reported. Research efforts should exploit
what is known about those drugs that have shown
potential in open-label studies for various pain syn-
dromes related to MS, such as central neuropathic pain
treated with lamotrigine, gabapentin, and levetiracetam,
trigeminal neuralgia treated individually or in combina-
tion with lamotrigine and gabapentin, and painful tonic
spasms treated with gabapentin and botulinum toxin. It
is also difficult to identify pharmaco-naive patients,
particularly in trigeminal neuralgia. Further, for ethical
reasons it is not possible to design placebo studies in
severe pain syndromes, which would essentially deny a
subject of pain relief when a potentially effective med-
ication is available. This type of effort would only be
possible through multicenter trials that would ensure
adequate subject samples.
MS does not occur in isolation, and comorbidities are
common, particularly in the aging segment of the MS
population. Clinicians should be aware that pain may
have various origins and can be unrelated to MS [90].
Further, patients with MS may have difficulty describing
their pain experience, and pain scales are biased by a
number of factors, including psychological comorbidity
(i.e., depression), unrealistic expectations related to
treatment, and inadequate sleep [91, 92]. A recent study
used focus groups to assess how subjects describe their
pain experience [93]. MS patients in particular used
various symbolic descriptors to express pain quality
not found on the frequently used McGill Pain Question-
naire, suggesting that pain assessment is complex and
should be based on patient experience [93, 94].
Recommendations for effective pain management in MS
will depend on the development of multiple-arm, random-
ized clinical trials, with adequate numbers of subjects with
specific pain characteristics [88]. In the meantime, it is
important for clinicians to evaluate the patient for pain at
each visit, keeping in mind that the same patient can expe-
rience different types of pain concurrently, thus making
differential diagnosis important. Finally, patients with MS
are at higher risk of adverse effects from pain medications
than the general population and frequently experience
comorbidities that can distort the clinical assessment, par-
ticularly depression and fatigue.
Disclosure No potential conflicts of interest relevant to this article
were reported.
Page 7 of 9, 320
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