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Pain associated with multiple sclerosis: Systematic review and proposed classification

Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Pain (Impact Factor: 5.21). 08/2008; 137(1):96-111. DOI: 10.1016/j.pain.2007.08.024
Source: PubMed
ABSTRACT
Pain is common in patients with multiple sclerosis (MS), but estimates of its prevalence have varied widely. The literature describing pain in MS patients spans four decades and has employed a range of different methodologies. We undertook a systematic review in order to summarize current understanding of the association between MS and pain and provide a basis for the design and interpretation of future studies. The point prevalence of pain in patients with MS is nearly 50%, and approximately 75% of patients report having had pain within one month of assessment. Pain adversely affects most aspects of health-related quality of life, including functional domains such as the ability to work. The presence of pain in patients with MS is associated with increased age, duration of illness, depression, degree of functional impairment, and fatigue. Several different types of pain are found in patients with MS, including extremity pain, trigeminal neuralgia, Lhermitte's sign, painful tonic spasms, back pain, and headache. Putative mechanisms of pain in patients with MS are discussed, and a classification of pain in MS is proposed. Few randomized clinical trials of treatments for MS pain have been conducted, and the limitations of current knowledge regarding approaches for treating MS pain are discussed. Suggestions for future studies that would increase understanding of the natural history, mechanisms, and treatment of pain in patients with MS are presented.

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Pain associated with multiple sclerosis: Systematic review
and proposed classification
Alec B. O’Connor
a
, Steven R. Schwid
b
, David N. Herrmann
b
,
John D. Markman
c
, Robert H. Dworkin
b,d,
*
a
Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA
b
Department of Neurology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA
c
Department of Neurosurgery, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA
d
Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA
Received 24 January 2007; received in revised form 8 July 2007; accepted 20 August 2007
Abstract
Pain is common in patients with multiple sclerosis (MS), but estimates of its prevalence have varied widely. The literature describ-
ing pain in MS patients spans four decades and has employed a range of different methodologies. We undertook a systematic review
in order to summarize current understanding of the association between MS and pain and provide a basis for the design and inter-
pretation of future studies. The point prevalence of pain in patients with MS is nearly 50%, and approximately 75% of patients
report having had pain within one month of assessment. Pain adversely affects most aspects of health-related quality of life, includ-
ing functional domains such as the ability to work. The presence of pain in patients with MS is associated with increased age, dura-
tion of illness, depression, degree of functional impairment, and fatigue. Several different types of pain are found in patients with
MS, including extremity pain, trigeminal neuralgia, Lhermitte’s sign, painful tonic spasms, back pain, and headache. Putative mech-
anisms of pain in patients with MS are discussed, and a classification of pain in MS is proposed. Few randomized clinical trials of
treatments for MS pain have been conducted, and the limitations of current knowledge regarding approaches for treating MS pain
are discussed. Suggestions for future studies that would increase understanding of the natural history, mechanisms, and treatment of
pain in patients with MS are presented.
Ó 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Keywords: Multiple sclerosis; Chronic pain; Neuropathic pain; Health-related quality of life
1. Introduction
Multiple sclerosis (MS) is a chronic, incurable dis-
ease, affecting 350,000 individuals in the United States
and millions worldwide [14]. Pain is common in patients
with MS, and it has recently been recognized as an
important factor in their overall health-related quality
of life (HRQoL) [48,95], the two most important com-
ponents of which are physical and emotional function-
ing [45,99].
Estimates of the prevalence of pain in MS have ran-
ged from 29% [17] to 86% [93]. Although a number of
studies have examined pain in patients with MS, the
methods used, patient populations studied, and defini-
tions of pain have varied widely. Furthermore, a recent
systematic review concluded that there is insufficient evi-
dence to adequately assess the safety and efficacy of dif-
ferent treatments for MS-related pain [8].
We conducted a systematic review of the literature to
(1) summarize current understanding of the prevalence,
0304-3959/$32.00 Ó 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.pain.2007.08.024
*
Corresponding author. Address: Department of Anesthesiology,
University of Rochester School of Medicine and Dentistry, 601
Elmwood Avenue, Rochester, NY 14642, USA. Tel.: +1 585 275 3524;
fax: +1 585 473 5007.
E-mail address: robert_dworkin@urmc.rochester.edu (R.H. Dwor-
kin).
www.elsevier.com/locate/pain
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impact on HRQoL, and mechanisms of pain in MS; (2)
propose an evidence-based classification of the most
common pain conditions associated with MS; and (3)
identify high priority areas for future research.
2. Methods
We performed a search of PubMed, the Cochrane Data-
base of Systematic Reviews, Database of Abstracts of
Reviews of Effects, and ACP Journal Club combining multi-
ple sclerosis (exploded) AND pain (exploded); additional
searches were performed combining multiple sclerosis AND
neuralgia or dysesthesia or dystonia or Lhermitte. This
search was limited to English language publications, and
yielded a total of approximately 900 articles, which were
reviewed by title and abstract for potential relevance to this
topic; when the title and abstract did not clearly indicate the
degree of relevance to the topic, the article itself was
reviewed. Bibliographies of topic-appropriate articles were
also examined to discover additional references not identified
in the primary search. Finally, the authors’ personal knowl-
edge of the literature was used to supplement the above ref-
erences. The methodologic quality of research studies was
assessed by the study authors. When multiple studies exam-
ining a specific research question were identified, prospective
studies involving patients with definite MS and using clear
definitions of pain conditions were prioritized over those
using other research methods.
3. Results
A total of 140 articles were considered to have
potential relevance to the topic and were reviewed in
detail. Several factors made comparison between differ-
ent studies difficult: (1) studies defined pain differently,
with some requiring a specific pain duration or severity
(e.g., pain duration of at least one month or pain that
is at least moderate in severity), and others not specify-
ing the criteria used to determine the presence of pain;
(2) specific pain conditions were referred to using vary-
ing terminology and were defined differently or not
defined at all; (3) the duration of time within which
pain was considered present varied from present at
the time of assessment to present at any time, but
sometimes was not specified; (4) some studies included
any type of pain while others excluded certain types of
pain from consideration, such as headache, ‘‘minor
pain relieved by analgesics,’’ ‘‘visceral pain,’’ or chronic
pain due to a concomitant diagnosis; (5) study samples
were diverse (e.g., population cohorts , nursing home
admissions, or hospitalized patients), with demographic
factors varying substantially among studies; (6)
research methods differed, including mail surveys,
administrative database queries, and in-person histories
and examinations; (7) widely disparate sample sizes
were examined; and (8) the use of comparison groups
or reference populations was uncommon.
3.1. Prevalence of pain in patients with MS
Twenty-one studies reporting the prevalence of pain
in patients with MS were identified, but two studies were
excluded because they were subset analyses of already
described patients [15,93]. Prevalence estimates ranged
from 29% to 86%.
In order to obtain a more precise estimate of the
prevalence of pain in patients with MS, studies meeting
specific criteria were examined. The criteria deemed
most important in determining the prevalence of pain
in MS patients were: (1) diagnoses of definite MS; (2)
prospective study design; and (3) clear description of
how pain was assessed, the time span during which pain
was evaluated, and the criteria for considering pain to be
present. Nine studies met these criteria (Appendix A)
and are discussed further in this section. Three of these
studies reported the prevalence of pain at any point dur-
ing the course of the patients’ MS [42,68,92], which ran-
ged from 57% to 65%. Additional studies examined the
clinically-relevant time points of pain at the time of the
evaluation, pain during the past month, and pain at dis-
ease onset.
3.1.1. Pain at the time of evaluatio n
Although only one study examined the prevalence of
pain in community-dwelling patients with MS at the
time of evaluation, it was a multicenter study with
face-to-face interviews of 1672 patients. The authors
reported that 43% of patients had pain at the time of
evaluation [90], excluding headache, optic neuritis pain,
and ‘‘somatic pain other than back pain.’’
Using interviews, two studies determined the preva-
lence of pain at the time of assessment in hospitalized
patients with MS. One study reported that pain was
present in 45% of acutely hospitalized MS patients
[92], excluding headache and ‘‘minor pain relieved by
analgesics.’’ The other study found that 54% of patients
with MS hospitalized for rehabilitation had pain [100],
excluding headache and ‘‘visceral pain.’’
3.1.2. Pain within one month of assessment
Three studies determined the prevalence of pain
during the month prior to assessment. Svendsen
et al. [96] examined prevalence in a geographically-
defined population cohort in Denmark using a mailed
survey (81% response rate), finding pain in 79% of
patients with MS. Archibald et al. [4] studied consec-
utive MS clinic referrals using the same pain definition
but with an in-person survey, and obtained a preva-
lence of 53%. Finally, Beiske et al. [9] used in-person
assessments and the same definition of pain but
excluded headache, obtaining a prevalence estimate
of 66%. Setting aside the differences in patient popula-
tions studied, survey methods , and the exclusion of
headache in one of the studies and pooling these
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patients together, three-quarters (633/854) of the out-
patients with definite MS who were surveyed had pain
within one month of assessment.
An additional study reported the prevalence of pain
that was ‘‘constant or nearly constant in the previous
month’’ [48] . This study, which excluded patients with
chronic pain caused by an illness other than MS or
trauma, found that 69% of patients met this definition
of chronic pain based on an in-person evaluation. In
contrast, Archibald et al. [4] reported that only 18% of
the patients they interviewed had ‘‘continuous pain’’
over the prior month. It is unclear why the Kalia et al.
[48] estimate is so much higher, but the prevalence of
constant pain in the past month would not be expected
to be higher than the 43% prevalence of any pain at the
time of assessment [90].
3.1.3. Pain at disease onset
Three studies assessed the prevalence of pain at dis-
ease onset, obtaining this information retrospecti vely
from patients an average of 8, 11, and 13 years after
onset. The patient populations and exclus ion criteria dif-
fer, but these studies reported that 23% [92], 21% [42],
and 11% [48] of patients had pain at the onset of their
MS. It is unclear from the description of these studies
whether disease onset referred to the diagnosis of MS
or the onset of MS symptoms.
3.1.4. Pain in patients with MS compared to control
subjects without MS
Pain in MS patients has been compared with pain in
persons without MS in several studies. Svendsen et al.
[96] found that pain within the past month was
reported by similar proportions of MS patients and
age- and sex-stratified control subjects (79% vs. 75%,
respectively). However, the MS patients were more
likely to have moderate or severe pain, to use analge-
sics, and to describe pain interference with activities
of daily living. Three studies found that MS patients
seem to have worse SF-36 bodily pain scores than
age- and sex-matched historical controls [25,48,63],
though the results of a fourth study contradict this
finding [72]. One study also compared MS patients’
SF-36 bodily pain scores with those of rheumatoid
arthritis and osteoarthritis patients, finding that all
three groups had comparable levels of pain severity
[48]. Another study compared MS patients’ pain to
patients with spinal cord injury, finding slightly but sig-
nificantly less pain in the MS patients [25]. Two studies
used the Minimum Data Set (MDS) to demonstrate
that, upon admission to nursing homes, MS patients
are slightly more likely to have pain than non-MS
patients [14,62]. No studies have compared the pain
experience of MS patients with non-MS patients
matched by level s of disease burden and health care
utilization.
3.2. Pain severity
The pain severity of MS patients with pain has been
described in several studies. Using a 0–10 numerical rat-
ing scale, the average pain intensity in patients with MS
who have pain was found to be moderate in four studies,
ranging from 4.8 to 5.8 [4,24,25,102], whereas two other
studies reported that most patients with pain rated its
severity as ‘‘mild’’ [96] or, on average, only 2.8 [48].It
is possible that differences in survey technique or other
methodology resulted in increased capture of mild pain
in the latter two studies, which would also account for
the relatively high prevalence of pain in these two sam-
ples when compared to seemingly similar studies.
Among 7579 respondents to a North American
Research Committee on MS (NA RCOMS) survey who
had experienced pain in the past month, 49% reported
their worst pain to be severe, 24% moderate (5–6 on a
0–10 scale), and 27% as mild [35].
Two additional studies analyzed the MDS in slightly
different nursing home populations; both found that
58% of MS patients had moderate pain, and that
another 15% [14] and 12% [62] had pain that was, at
times, horrible or excruciating. Patients in one study
experienced an average of 77 hours of pain per week
[4]. One-third of patients characterized pain as one of
the worst symptoms of MS [92], although only 5% of
patients in another study selected pain as their worst
symptom [75].
3.3. Pain impact on HRQoL
The presence of pain is associated with poorer
HRQoL in MS patients [30,48,95]. In MS patients
who ha ve pain, greater pain severity is associated with
poorer HRQoL [30,48], including greater interference
with daily life [24,30], poorer functioning on most com-
ponent scales of the SF-36, including bodily pain, gen-
eral health, role emotional, energy/vitality, mental
health, and social functioning [30], and increased inter-
ference in each component of the Medical Outcomes
Study pain effects scale (mood, ability to walk or move
around, sleep, normal work, recreational activities,
and enjoyment of life) [35].
Pain in patients with MS is associated with interfer-
ence in the two major components of HRQoL, physical
and emotional functioning [45,99]. Thirty percent of all
NARCOMS respondents reported at least moderate
pain interference (‘‘pain frequently affects some of my
activities, several times a week’’) [35]. In one study, pain
interfered with daily life ‘‘all’’ or ‘‘most’’ of the time in
42% of MS patients, compared to 19% of age- and
sex-matched controls [96] . Moderate to severe interfer-
ence with daily function has been reported in almost half
of MS patients with pain in two other studies [9,24].In
another study, the average Brief Pain Inventory (BPI)
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interference score (on a 0–10 scale) across all of the
domains was 3.4, with pain interfer ing most with sleep
and recreational activities [25]. Pain has also been found
to interfere substantially with the ability of patients with
MS to work [4,35,102], sleep [35,102], maintain relation-
ships [102], and enjoy life [35,72] .
3.4. Natural history of pain in patients with MS
One study has specifically documented the evolution
of pain (excluding headache and minor pain relieved
by analgesics) in a select group of 49 MS patients [93] .
Over a 5-year period, the prevalence of pain at the time
of evaluation increased from 35% to 78%, with the larg-
est increase occurring in ‘‘tension’’ and spasms of the
extremities. Unfortunately, the high prevalence reported
for the follow-up assessment is not consistent with the
prevalence found in other, much larger studies in less
selected populations, making the generalizability of
these results uncertain.
NARCOMS respondents with pain typically sought
care from neurologists or primary care physicians.
Although patient satisfaction with pain treatment corre-
lated inversely with pain severity, satisfaction was sur-
prisingly high in those patients with moderate and
severe pain (all groups 5.5–6.0 on a 0–10 scale) [35].
3.4.1. Factors associated with presence and severity of
pain in MS
A number of studies have compared MS patients with
pain to MS patients without pain in an effort to deter-
mine risk factors for the development of pain (Table
1). For many of the factors that have been assessed, at
least one study has reported an association with pain
but at least one other study shows no association. Since
the power to detect subgroup differences is directly
dependent on sample size, and many of the published
studies are small, we emphasize the results of larger
studies when the results of multiple studies are
inconsistent.
The risk factors reported to be associated with a
greater likelihood of pain in patients with MS include
older age [17,24,35,60,90,96], longer disease duration
[4,17,60,90], and greater disease severity as measured
by Expanded Disability Status Scale (EDSS) [24,25,90]
or the Patient-Determined Disease Steps [35]. Men and
women with MS seem to have a comparable risk for
pain [4,9,24,25,42,90,92], although wom en may have
greater severity of pain [35].
Patients with relapsing-remitting MS seem to have a
reduced risk of developing pain compared to those with
other types of MS [35,90]. In addition, nursing home-
dwelling MS patients with pain are more likely to
Table 1
Factors associated with pain in MS patients
Study Year Number
of patients
Greater MS
duration
Greater age
at survey
Greater age
of MS onset
Higher
EDSS
Female
sex
Non-relapsing
remitting
Worsened
emotional
function
Worsened
physical
function
Studies used in prevalence estimates
Solaro 2004 1672 Yes Yes NR Yes No Yes NR NR
Svendsen 2003 627 No Yes NR NR NR NR NR Yes
Osterberg 2005 364 No No NR NR NR NR NR NR
Beiske 2004 142 No No No No No NR NR Yes
Indaco 1994 122 No No NR No No NR No NR
Stenager 1991 117 No No NR No No NR NR NR
Kalia 2005 99 No No NR No NR No Yes No
Archibald 1994 85 Yes No NR No No No Yes Yes
Vermote 1986 83 NR NR NR No NR NR NR NR
Other studies
Hadjimichael 2007 15853 Inverse Yes NR Yes Yes
a
Yes Yes
a
Yes
Buchanan 2003 14009 NR NR NR NR NR NR Yes NR
Forbes 2006 929 NR NR NR NR NR NR Yes NR
Ehde 2003 442 NR Yes NR Yes No NR Yes Yes
Warnell 1991 364 No No No NR Yes No NR Yes
Clifford 1984 317 Yes Yes NR NR NR NR NR NR
Newland 2005 247 NR NR NR NR NR NR NR NR
Rae-Grant 1999 224 No NR NR No NR NR NR NR
Nortvedt 1999 194 NR NR NR No NR NR No NR
Ehde 2006 180 No No NR Yes No No Yes Yes
Moulin 1988 159 Yes Yes No No Yes NR NR NR
Svendsen 2005 100 No NR NR No NR Yes Yes Yes
Studies used for prevalence estimates are those with prospective research designs, patients with definite MS, and clear definitions of pain and the time
frame during which pain occurred. Studies are ordered according to the number of subjects because the power to detect associations is greater for
larger studies.
EDSS, expanded disability status scale; NR, not reported.
a
Factor associated with increased pain severity rather than the presence of pain.
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develop pressure ulcers than MS patients without pain
despite having similar activities of daily living scores
[62]. Finally, MS patients with depression or mental
health impairment are more likely to have pain
[4,15,24,25,30,48].
Greater pa in severity has been found to be associ ated
with increased disability, female sex, increased age,
depression, non-stable MS disease course, lower educa-
tional level, greater duration of pain, and greater health
care utilization [35]. Osborne and colleagues [66]
recently found that psychosocial factors (including
pain-related catastrophizing and pain coping) were not
only strongly associated with pain interference but were
also more strongly associated with pain intensity than
demographic and clinical variables (age, sex, and sever-
ity of MS).
An ‘‘interdependent relationship’’ between pain, fati-
gue, and depression in MS patients [30] has been
described, and recent data [66] provide support for a
biopsychosocial model of pain in MS [51]. Prospective
longitudinal studies are necessary, however, to deter-
mine whether depression and other psychosocia l charac-
teristics are risk factors for the development of pain in
patients with MS or whether emotional distress is a con-
sequence of chronic daily pain and increased disease
severity.
3.4.2. Effects of disease-modifying therapy on pain
Few studies have assessed the effects of diseas e-mod-
ifying treatments on pain in patients with MS. In one
study, 50% of patients reported improvement in pain
while receiving disease-m odifying therapy [38]. How-
ever, a study evaluating interferon beta treatment
reported that pain increased in the first month of treat-
ment then returned to baseline levels 3 and 6 months
later [5]. In addition, Po
¨
llmann et al. [74] reported that
interferon beta and glatiramer acetate treatment were
associated with an increase in the frequency and dura-
tion of headaches, especially in patients with pre-existing
headaches and those treated with interferon beta.
Among NARCOMS respondents, however, disease-
modifying therapy was not associated with greater pain
severity [35].
Pain has not been systematically assessed in clinical
trials examining the efficacy of treatmen ts intended to
improve disability and other outcomes in MS. This
would be especially important because early and possi-
bly transient increa ses in pain associated with disease-
modifying therapy could be offset by longer-term bene-
ficial effects of treatment in preventing or reducing pain.
3.5. Types of pain in MS
Several different pain conditions are associated with
MS. Different studies, using different definitions of spe-
cific pain conditions and different methods, have pro-
duced at times widely disparate estimates of the
prevalence of individual pain conditions. Pain has been
defined by location, by presumed mechanism (e.g., mus-
cle spasms, central pain), and by duration, ranging from
paroxysmal to chronic. Unfortunately, different investi-
gators have often used differing definitions of specific
pain conditio ns, or do not specify how such conditions
were defined. As discussed above for the overall preva-
lence of pain in MS, the duration of pain (e.g., pain
now vs. pain over the past month vs. pain ever) consid-
ered for specific pain conditions also varies from study
to study, and at times is not specified. Nevertheless, sev-
eral distinct pain conditions associated with MS have
been relatively clearly defined and characterized.
Optic neuritis is common in patients with MS and can
cause pain. Unfortunately, optic neuritis has been
excluded from consideration in some pain prevalence
studies [82,90] and many studies do not consider it at
all. In one study, 8% of patients had experienced pain
from optic neuritis at some point during their MS [42],
and in another study, none of 117 patients were experi-
encing pain from optic neuritis at the time of assessment
[92]. Further research is needed to determine how much
of a burden this source of pain is among MS patients.
Because very few studies have examined painful optic
neuritis and diagnostic criteria are controversial and
not widely used [1], this specific pain condition will not
be considered further in this article.
We discuss below a phenomenon that has been
described primarily in MS patients, painful tonic
spasms, but ordinary muscle spasms appear to be a
more common and disabling problem among MS
patients [8,20,79]. However, spasms are not always pain-
ful, and in one study the degree of spasticity was similar
for patients with and without pain [95]. We were unable
to identify studies specifically assessing pain associated
with muscl e spasms in patients with MS, for example,
quantifying how frequently pain coexists with spasms,
the severity of pain when present, or the change in pain
following treatment for spast icity. Research exploring
the relationship between muscle spasms and pain is
needed, and future RCTs should quantify changes in
pain following treatment.
3.5.1. Central neuropathic pain
One broad category of MS-related pain is central
neuropathic pain, of which there are several distinct
types. Osterberg et al. [68] defined central pain as pres-
ent if the distribution of pain was consistent with a cen-
tral nervous system lesion and a thorough evaluation for
nociceptive and peripheral neuropathic pain was nega-
tive, including a detailed history and physical exam,
focused blood tests, and electrophysiology; the authors
also required the absence of psychiatric disease, and
did not consider ‘‘pure back pain,’’ headache, or optic
neuritis to be central pain. Of a sample of 364 MS
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patients, 27.5% ha d what was considered definite central
neuropathic pain, including 18 with trigeminal neural-
gia, which is thought to be caused by central nervous
system lesions in patients with MS. Of these, 91% had
pain at the time of evaluation, and most had constant
daily pain. One-third of patients with central neuropath-
ic pain had two or more central neuropathic pain types
and locations. In most of the patients with central neu-
ropathic pain, pain affected the lower extremities: 62 of
the 100 patients had bilateral lower extremity pain, and
another 13 patients had unilateral lower extremity pain.
Nearly all patients had abnormal sensory exams, with
the most common abnormality being decreased cold
sensation, which the authors interpreted as support for
the hypothesis that central neuropathic pain in MS
patients often results from lesions in spinothalamocorti-
cal pathways.
Svendsen et al. [95] defi ned central pain as pain in a
neurologic distribution with altered sensation and no
history or clinical evidence of peripheral neuropathy.
In their sample of MS patients with pain of at least
one month duration and intensity P3 on a 0–10 scale,
58% (29/50) had central neuropathic pain. Many
patients had multiple areas of pain, with pain most com-
mon in the lower extremities (96%), back (70%), and
upper extremities (52%). All patients with central pain
had signs of spinothalamic dysfunction, and MS
patients with any type of pain had lower pressure pain
thresholds than MS patients without pain on quantita-
tive sensory testing.
On the basis of the results of these and other studies,
the most common central neuropathic pain conditions
in patients with MS are extremity pain, trigeminal neu-
ralgia, and Lhermitte’s sign.
3.5.1.1. Central neuropathic (‘‘dysesthetic’’) extremity
pain. Several studies have reported that central extremity
pain (often termed ‘‘dysesthetic’’ extremity pain) is the
most common type of pain associated with MS
[17,42,60,68,90,95,100]. The point prevalence of this
type of pain in patients with MS is approximately 17%
[90,92,100], with 11% of patients reporting extremity
pain at disease onset [42] and 23% reporting it at some
point during the course of their MS [42,68].
Central neuropathic extremity pain is usually a
chronic form of pain in patients with MS [42,60,68].It
is described as a continuous ‘‘burning’’ pain [17,60] that
is typically bilateral, affecting the legs and feet [48,60,68],
and that is usually worse at night [60] and can be exac-
erbated by physical activity [68]. This type of pain must
be distinguished from other conditions that could cause
bilateral extremity pain, including musculoskeletal pain
and pain associated with peripheral neuropathy. As dis-
cussed below, central extremity pain is thought to be
caused by lesions in spinal cord nociceptive pathways
affecting the inhibitory function of GABA interneurons.
Given its prevalence in patients with MS, additional
studies of the natural history, mechan isms, and treat-
ment of central neuropathi c extremity pain are needed.
3.5.1.2. Trigeminal neuralgia. Trigeminal neuralgia is rel-
atively common in patients with MS (Table 2). Two
large studies detected a prevalence of trigeminal neural-
gia in MS pa tients over a 13- to 15-year period of 1–2%
[41,83], roughly 20 times the preval ence of trigeminal
neuralgia in the general population. In patients with tri-
geminal neuralgia, the prevalence of MS is also much
higher than would be expected. Large, retrospective
population studies have detected MS in 2–8% of trigem-
Table 2
Relationship between trigeminal neuralgia and MS
Study Year Time frame Number
with TN
Number
with MS
Prevalence
(%)
Number with
bilateral TN
Percent of TN cases
that are bilateral (%)
MS patients
Rushton 1965 15 years 35 3880 0.9 4 11.4
Vermote 1986 Now 3 83 3.6 NR NR
Moulin 1988 During MS (13 years) 7 159 4.4 NR NR
Hooge 1995 13 years 35 1882 1.9 5 14.3
Eriksson 2002 40 years 5 255 2 NR NR
Solaro 2004 Now 36 1672 2.2 NR NR
Osterberg 2005 During MS (23 years) 18 364 4.9 2 11.1
Total 139 8295 1.7 11/88 12.5
TN patients
Rushton 1965 15 years 1735 35 2 4 11
Chakravorty 1966 14 years 124 10 8 0 0
Jensen 1982 33 years 900 22 2.4 7 32
Katusic 1990 40 years 75 3 4 NR NR
Total 2834 70 2.5 11/67 16.4
TN, trigeminal neuralgia; NR, not reported; ‘‘Now,’’ at the time of assessment.
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inal neuralgia patients [16,46,52,83], with a weighted
average of 2.6% (73/283 4), again 20 times the expected
prevalence.
In MS patients, 11–31% of trigeminal neuralgia cases
are bilateral, a much higher rate than in non-MS
patients [12,41,46,83]. M S patients who develop trigem-
inal neuralgia tend to be younger than non-MS patie nts
with trigeminal neuralgia [22,46,83] and are less likely to
have an ophthalmic nerve distribution than non-MS
patients [12,22]. In one series, trigeminal neuralgia was
the presenting symptom of MS in 14% (5/35) of trigem-
inal neuralgia cases [41].
3.5.1.3. Lhermitte’s sign. Lhermitte’s sign, which is actu-
ally a symptom rather than a sign, has been defined as
‘‘a transient short-lasting sensation related to neck
movement... felt in the back of the neck, lower back
or in other parts of the body’’ [2]. It has been associated
with MRI lesions in the posterior columns of the cervi-
cal spinal cord [2,34], and is thought to be caused by
hypersensitivity of demyelinated cervical sensory axons
to stretching [49].
The prevalence of Lhermitte’s sign at the time of eval-
uation in two recent studies ranged from 9% to 13%
[2,90], although smaller, less-rigorous studies have
described a much broader range of estimates. Two pro-
spective studies found Lhermitte’s sign to have been
present at some point during the course of MS in 40%
of patients [2,49], with one study also finding no cases
among healthy controls [2]. Nearly all patients reported
that neck flexion brought the symptom on, and a few
reported that other positions can also elicit Lhermitte’s
sign [2,49]. Patients with Lhermitte’s sign most com-
monly described the symptom as ‘‘electric’ or like an
‘‘electric shock’’ lasting less than 2 s, with immediate
relief upon cessation of neck flexion [2,49]. Nearly all
patients experienced Lhermitte’s sign in the neck, and
two-thirds also felt it in the low er back, with some
reporting symptoms in one or more limbs as well
[2,49]. One-quarter of patients with Lhermitte’s sign
had never told their physicians [2,49], and none of the
patients with Lhermitte’s sign had asked for treatment
of this symptom during their illness [2,49]. In most
patients, the symptom resolved over 4–6 weeks, but in
some it recurred occasionally, especially during MS
exacerbations [49].
3.5.2. Painful tonic spasms
As in many uppe r motor neuron disorders, muscle
spasms are common in patients with MS [8,20,79] and
they can be painful. A specific type of episodic sp asm
associated with MS is called ‘‘painful tonic spasms’’
(PTS). EEGs performed during the episodes do not
reveal epileptiform discharges [89,104], making ‘‘spasm’’
or ‘‘dystonia’’ more appropriate descriptors than the
older term ‘‘painful tonic seizures.’’ Case series indica te
that PTS usually occur several times per day, last less
than 2 min each, seem to be stereotypical, can be pre-
ceded by a ‘‘somesthesic aura,’’ and can be triggered
by touch, movement, hyperventilation, or emotions
[57,89,91]. PTS can be chronic or can remit over days
to months, and in some cases pain immediately precedes
the spasms, suggest ing that pain may not be caused by
the muscle spasm itself [57,89]. A relatively small retro-
spective cohort analysis described an association
between Lhermitte’s sign and PTS [53]. MRI lesions
associated with PTS have been demonstrated in the
basal ganglia, internal capsule, cerebral peduncle,
medulla, and spinal cord [91], and symptoms are
thought to result from ephaptic spread of spontaneous
discharges generated by demyelinated axons [77].
In many studies, the criteria used to define PTS were
not described. Further complicating interpretation of
the literature, paroxysmal spasms are not always pain-
ful, whi ch likely accounts for the use of broader terms
such as ‘‘paroxysmal spasms,’’ ‘‘paroxysmal dystonia,’’
‘‘tonic spasms,’’ ‘‘tonic seizures,’’ and ‘‘muscle spasms.’’
In fact, pain is prominent in less than half of patients
with ‘‘tonic seizures,’’ ‘‘paroxysmal seizures,’ or ‘‘par-
oxysmal dystonia’’ [10,57,69]. These factors make it dif-
ficult to interpret the widely varying estimates of the
prevalence and impact of pain associated with PTS.
3.5.3. Back pain
The prevalence of back pain in MS patients has ran-
ged from 10% to 16% [35,42,48,60,68,90]
. In many MS
patients with back pain, the pain is musculoskeletal in
origin and aggrava ted by prolonged standing or sitting.
In one study, back pain was associated with scoliosis
and degenerative joint disease on spinal X-rays [60],
although it is possible that these findings were not spe-
cifically associated with MS. In some patients back pain
can be central in origin [68,95].
3.5.4. Headache
Headache has been reported to be more common in
patients with MS than the general population. Two pro-
spective studies have specifically assessed the frequency
of headache in MS patients and found substantially
higher prevalence estimates than studies that did not
focus on headache (Table 3). Rolak and Brown [82]
determined that 54% of newly diagnosed MS outpa-
tients had headache, compared to only 14% of patients
suspected to have MS but ultimately found not to have
it and only 18% of age-, sex-, and disability-matched
general neurology patients. In a cohort of MS patients,
41% of headaches were classified as migraine (22% of
total MS patients) and the remainder as ‘‘muscle con-
traction headaches.’’ The authors also noted that head-
ache symptoms did not correlate with MS symptoms.
Watkins and Espir [103] found migraine in 27% of MS
patients, compared to 12% of age- and sex-matched hos-
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pital visitors. Neither of these studies specified the time
interval over which headaches were evaluated, but other
studies have reported the prevalence of headache in MS
patients to be 13% [15] and 12–22% [35,48] within one
week and one month, respectively.
Freedman and Gray [31] reported an association
between the development of migraine and the onset or
exacerbation of MS. Migraine headache was the present-
ing symptom of MS in 1.6% (18/1100) of patients in their
sample; another 26 patients (2.3% of total) developed
migraines with the onset of MS exacerbations.
Two studies have reported that interferon beta treat-
ment is associated with an increa se in headache fre-
quency and severity [54,74], especially during the first
few months of therapy [74]. There is some evidence that
glatiramer and azathioprine may not increase headache
to the same extent as interferon beta [54,73,74], but
additional research in this area is needed.
3.6. Studies addressing the mechanisms of pain in patients
with MS
Specific mechanisms underlying pain in MS have not
been identified. However, several investigators have
characterized the neuroanatomy and physiology associ-
ated with painful conditions in MS patients, and these
findings provide a basis for developing hypotheses about
the mechanisms of pain in MS.
3.6.1. Imaging studies
In a series of MS patients with well-defined central
neuropathic pain (as described in Section 3.4.1) who
underwent MRI, each patient had between five and 16
focal lesions in the brain, with lesions tending to be less
than 1 cm in size and located in the periventricular white
matter; one-third of these patients had lesions in the lat-
eral and medial thalamic regions. Furthermore, almost
all patients undergoing cervical and thoracic spine
MRI also had lesions in the spinal cord [68]. Because
such MRI findings are common in patients with MS,
the relationship between these findings and pain remains
to be established.
An MRI series of five patients with PTS found that
all had a probably causative lesion either in the motor
pathway at the level of the internal capsule posterior
limb or in the cerebra l peduncle; the authors con-
cluded that the close proximity of motor fibers in
these locations allowed for the ‘‘radial spread of eph-
aptic activation’’ from a lesioned area to normally
functioning motor fibers, resulting in stereotypical
muscle spasms [91].
Two series have found that most patients with Lher-
mitte’s sign who had undergone cervical MRI had
lesions in the cervical spinal cord; patients with MS
without Lhermitte’s sign were much less likely to have
cervical lesions [2,34] .
MRI findings support the conclusion that MS
lesions at the trigeminal nerve root entry zone account
for at least some cases of trigeminal neuralgia in
patients with MS [32,58], a lthough some MS patients
have lesions in this region without trigeminal neural-
gia [21]. Two case series found an association between
trigeminal neuralgia and specific MRI abnormalities
considered structurally similar to animal models with
herpes simplex virus infection: T1-weighted-hypoin-
tense, T2-weighted-hyperintense, non-enhancing linear
lesions in the pons located at the intramedullary por-
tion of the trigeminal root [27, 61].
3.6.2. Quantitative sensory testing
Several studies have used quantitative sensory testing
(QST) to evaluate sensory function and abnormalities in
Table 3
Relationship between headache and MS
Study Year Time
frame
Prospective/
retrospective
Number
with MS
Number
with HA
Percent of MS
patients
with HA (%)
Number
with
migraine
Percent of MS
patients with
migraine (%)
Number of MS
patients with
tension HA
Percent of
MS patients
with tension
HA (%)
Dedicated headache studies
Watkins 1969 NR Retrospective 100 NR NR 27 27.0 NR NR
Rolak 1990 NR Retrospective 104 54 52 22 21.2 32 30.8
Po
¨
llmann 2002 NR Prospective 65 32 49 23 35.4 8 12.3
Total 269 86 50.9 72 26.8 40 23.7
General pain prevalence studies
Clifford 1984 7 years Retrospective 317 17 5.4 10 3.2 7 2.2
Kassirer 1987 During MS Prospective 28 16 57 NR NR NR NR
Moulin 1988 During MS Prospective 159 30 18.9 4 2.5 26 16.4
Buchanan 2003 Week Retrospective 14,009 1832 13.1 NR NR NR NR
Kalia 2005 Month Prospective 99 22 22 NR NR NR NR
Total 14,612 1917 13.1 14 2.9 33 6.9
HA, headache; NR, not reported.
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central nervous system sensory pathways. In a study
examining various types of pain in MS, QST findings
were generally similar in patients with and without
chronic pain except that those with pain had lower pres-
sure pain thresholds, regardless of whether they had cen-
tral neuropathic pain or musculoskeletal pain [95].
Patients with central pain did not differ from those with
musculoskeletal pain in the results of QST, but those
with central pain were more likely to have cold or
mechanical allodynia on bedside sensory examination.
The authors concluded that sensory hyperexci tability
and spinothalamic dysfunction are more common in
MS patients with pain, especially those with central
pain, and that there is also evidence that dorsal col-
umn-medial lemniscal pathways can be affected.
In another series of MS patients with central neuro-
pathic pain evaluated with QST, nearly all patients had
alterations in temperature or pain sensation in the painful
region [67]. A case report of QST in an MS patient with
central pain found tactile allodynia, heat hypalgesia, cold
allodynia, and, in contrast to healthy control s, no pain
from the thermal grill (intermixed 20 °C and 40 °C stim-
uli); the authors hypothesized that interruption of ther-
mosensory pathways may impair normal cold inhibition
resulting in central burning pain [59].
3.6.3. Other methodologic approaches
Autopsies of patients with MS and trigeminal neural-
gia have demonstrated plaques involving the trigeminal
nuclei and the trigeminal nerve root entry zone of the
pons [46,55,56,65]. Two case reports of MS patients with
trigeminal neuralgia who underwent brainstem auditory
evoked potentials found abnormalities consistent with
an area of demyelination involving the right trigeminal
sensory root and right lateral lemniscus [37,44], one of
which was confirmed by MRI [37].
Two patients with painful feet who were initially eval-
uated for peripheral neuropathy but ultimately found to
have MS as the likely cause of their pain were found to
have normal sural sensory and peroneal motor nerve
conduction studies and normal intraepidermal nerve
fiber density on skin biopsy [70]. In a series of 62 MS
patients with central pain, none had evidence of nerve
root pathology or polyneuropathy on nerve conduction
studies [68].
Positive symptoms such as Lhermitte’s sign and PTS,
which are thought to be caused by ectopic impulses
resulting from demyelination and axonal damage, have
been shown to decrease with intravenous lidocaine (pre-
sumably due to sodium channel blockade); in contrast,
negative symptoms (e.g., paresis and hypesthesia) were
exacerbated by lidocaine [84]. Intrathecal baclofen
reduced extremity pain in a series of four MS patients,
which prompted the authors to suggest that dysfunction
of the GABA receptor system, including ‘‘functional
hypersensitivity,’’ contributed to this type of pain [40].
3.7. Proposed classification of pain in patients with MS
The proposed classification of pain in patients with
MS that follows is largely based on phenomenology. It
includes hypotheses about underlying pathophysiologic
mechanisms that might ultimat ely serve as the founda-
tion for a mechanism-based classification of pa in in
MS [106]. Our intention is to present a framework for
generating research hypotheses and data that will ulti-
mately provide the foundation for an evidence-based
approach to identifying mechanisms of pain in patients
with MS (Table 4). Distinguishing whether pain is pri-
marily neuropathic or non-neuropathic is a critical fea-
ture of this framework, one which may have important
treatment implications. Although chronic pain associ-
ated with MS is often neuropathic, in many patients
there can be a somatic or inflammatory component;
for example, demyelination and the disability it causes
may ultimately cause chronic low back pain that local-
izes to muscle and ligamentous tissue. Clinical trials that
identify and then target specific pain mechanisms may
be more successful at identifying efficacious treatments
than those in which patients with a variety of different
pain mechanisms are studied.
In classifying pain associated with MS, it is important
to dist inguish pain caused by damage to somatosensory
pathways vs. upper motor neuron tracts. As with central
post-stroke pain, there are pain conditions in MS with
predominantly sensory features and others marked by
motor symptoms, such as spasticity. On the basis of cur-
rent approaches to the diagnosis of neuropathic pain
[11,43,98], we have not considered pain to be neuropath-
ic when it is indirectly caused by lesions of the nervous
system. An additional distinction between ‘‘primary’’
and ‘‘secondary’’ pain in MS can be used to refer to
types of pain that are associated with MS lesions vs.
those that are an indirect consequence of MS lesions,
such as pain caused by disease-modifying treatment.
3.7.1. Continuous central neuropathic pain
MS causes demyelination and axonal damage in the
brain and spinal cord, leading to distinct mechanisms
that have been hypothesized to cause central neuropath-
Table 4
Proposed classification of pain conditions associated with multiple
sclerosis
Pain condition Example
Continuous central
neuropathic pain
‘‘Dysesthetic’’ extremity pain
Intermittent central
neuropathic pain
Lhermitte’s sign, trigeminal neuralgia
Musculoskeletal pain Painful tonic spasms, low back pain,
muscle spasms
Mixed neuropathic and
non-neuropathic pain
Headache
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ic pain. MS lesions that cause central hyperexcitability
and disruption of spinothalamic pathways may account
for continuous central extremity pain. Damage of this
type in MS appears to result in disinhibition, perhaps
especially of the ‘‘cold inhibition of pain,’’ and continu-
ous pain that is burning and/or throbbing in quality
[18,59,68,85], which is how dysesthetic extremity pain
is general ly described by patients with MS. Because cen-
tral pain in MS often manifests bilaterally in the low er
extremities, the causative lesion is likely to be in the
spinal cord in many cases [19,68].
3.7.2. Intermittent central neuropathic pain
Demyelination in patients with MS can also cause
ectopic impulses in damaged neurons, wi th ep haptic
spread to normally conducting neurons. Depending on
the location of the lesions, such abnormalities in
somatosensory pathways can be hypothesized to pro-
duce the intermittently painful conditions that occur in
patients with MS, including trigeminal neuralgia and
Lhermitte’s sign.
3.7.3. Musculoskeletal pain
Lesions affecting motor neurons may result in the
involuntary, intermittent painful muscle contractions
characteristic of PTS. Although this type of pain is
caused by demyelination, it would not be considered
neuropathic pain according to current diagnostic criteria
because the nerve damage does not appear to affect
somatosensory pathways [11,98].
By causing weakness, muscle spasms, and spasticity,
as well as reducing mobility, MS predisposes patients
to developing secondary musculoskeletal pain, especially
in the lower back. Treatment of MS can also produce
secondary musculoskeletal pain; for example, interferon
beta often causes myalgias, and chronic steroid use can
cause osteoporosis resulting in, for example, vertebral
compression fractures.
3.7.4. Mixed neuropathic and no n-neuropathic pain,
especially headache
Some types of chronic pain associated with MS do
not readily fit into one of the above categories. Head-
ache (including migraine) in patients with MS is one pre-
valent example of such pain conditions, which likely
involve a complex mixture of neuropathic, inflamma-
tory, and musculoskeletal mechanisms [11].
3.8. Treatment of pain in patients with MS
Few randomized, double-blind, placebo-controlled
trials of pain treatments have been performed in patients
with MS. A systematic review published in 2003 con-
cluded that there were no RCTs specifically designed
to assess an intervention for pain relief in MS patients,
and that function and quality of life outcomes should
be assessed in future trials [8]. The authors did conclude
that there was evidence that botulinum toxin, intrathecal
baclofen, and, to a lesser extent, four oral drugs (baclo-
fen, dantrolene, diazepam, and tizanidine) reduce spas-
ticity and improve function, although the effects of
these treatments on pain had not been specifically
studied.
Since this review was published, five RCT s assessing
the use of cannabinoids for pain in patients with MS
have been published. Using a crossover design, the oral
synthetic delta-9-tetrahydrocannabinol (THC) dronabi-
nol reduced pain and improved certain HRQoL mea-
sures but was associated with a high frequency of side
effects [94]. In a parallel group trial, a mixture of THC
and can nabidiol reduced pain, improved sleep quality,
and was reasonably well tolerated [80]. A third trial
found that THC, alone and in combination with canna-
bidiol, relieved pain more than placebo in patients with
chronic pain, although less than half of these patients
had MS [64]. The combination of THC and cannabidiol
was evaluated for the treatment of MS patients’ ‘‘most
troubling’’ symptom, whether spasticity, bladder prob-
lems, tremor, or pain. Among the 36 (of 160) patients
who reported pain as their most troubling symptom,
there was no statistically significant benefit compared
to placebo [101]. Finally, the synthetic cannabinoid nab-
ilone was studied in a crossover trial involving 13 MS
patients; it was found to reduce spasticity-related pain
and was reasonably well tolerated, but it did not
improve spasticity or motor function [105]. Side effects
may have compromised the blinding in some of these tri-
als, which would make interpretation of the results
problematic; this possibility should be evaluated in
future studies.
The results of these clinical trials suggest that cannab-
inoids might be effective in some patients with MS pain,
although to establish the efficacy and safety of this class
of medications further research is required, especially
large, well-controlled Phase III trials. Because of con-
cerns about their long-term safety, including concerns
involving precipitating psychosis or schizophrenia, espe-
cially in individuals with environmental or genetic risk
factors [88], these agents have been considered second-
line in the treatment of central neuropathic pain, includ-
ing MS pain [7]. A recent consensus guideline for the
treatment of symptoms associated with MS also does
not recommend cannabinoids [39].
Until additional studies are condu cted evaluating
treatments for MS pain, the results of the few RCTs
conducted in patients with other common central neuro-
pathic pain conditions specifically, post-stroke and
spinal cord injury pain and in patients with peripheral
neuropathic pain can guide the treatment of neuropathic
pain associated with MS [7,23,28,29]. Gabapent in, pre-
gabalin, lamotrigine, and tricyclic antidepressants have
each been recommended for the treatment of central
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pain based on efficacy in one or more RCTs [7,29].Itis
also reasonable to consider treating MS-related neuro-
pathic pain with medications for which there is evidence
of efficacy in patients with peripheral neuropathic pain,
specifically, opioid analgesics, tramadol, and the selec-
tive serotonin and norepinephrine reuptake inhibitors
duloxetine and venlafaxine [23,29].
On the basis of older clinical trials and extensive clin-
ical experience in non-MS patients, carbamazepine is
generally considered the first-line medication for the
treatment of trigeminal neuralgia [7,29]. Although neu-
rovascular decompression is effective in some MS
patients with trigeminal neuralgia [6], it appears to be
less effective in MS patients than in patients with trigem-
inal neuralgia who do not have MS [13].
Disease-modifying treatment with interferon beta
produces a flu-like syndrome in the majority of MS
patients, including myalgias and headache. The benefits
of peri-interferon acetaminophen, ibuprofen, and pred-
nisone have been compared in two studies, but there
were no differences between these medications for
post-interferon flu-like symptoms [76,78].
4. Discussion
The available evidence suggests that pain is common
among patients with MS, affecting as many as one in
five patients at disease onset, approximately half of
patients at any given point in their disease, and up to
three-quarters of patients within the preceding month.
Importantly, pain in patients with MS is associated
with decreased HRQoL, including impairments in
physical and emotional functioning. Several different
types of pain associated with MS can be identified,
including continuous central neuropathic pain, inter-
mittent central neuropathic pain, muscul oskeletal pain,
and mixed neuropathic and non-neuropathic pain.
These types of pain should be distinguished in future
studies, which should also clearly describe how pain
was assessed and the time span during which pain
was evaluated.
Several aspects of pain in patients with MS require
further study. Comparison of the pain experience of
MS patients and non-MS patients with similar associ-
ated disability and health care utilization would allow
clarification of the degree to which pain is attributable
to MS. Whether race and ethnicity are associated with
pain in MS has not been adequately studied. Although
depression and psychosocial risk factors are associated
with MS-related pain, it is unclear whether they are risk
factors for the development of pain or if they result from
pain; future research is needed to clarify the relation-
ships between pain and depression, fatigue, and cogni-
tive de ficits in patients with MS [30,47,71,86,87].
Improved methods for assessing pain in MS are needed,
and the roles of patient questionnaires (e.g., [81]), phys-
ical examination and bedside sensory testing, and QST
should be clarified [36]. Certain types of pain that seem
to be associated with MS have not been well character-
ized, including pain associated with optic neuritis and
pain related to muscle spasms. In addition, surprisingly
little is known regarding the relationships between clin-
ical exacerbations of MS and the occurrence, type, and
intensity of pain.
Further identification and characterization of the
mechanisms of the different types of pain that occur in
patients with MS is needed, particularly for extremity
pain, the most common type of pain in MS. Such
research has the potential to provide the foundation
for improving classification of pain in patients with
MS and for identifying mechanism-based treatments
[106]. Because little is known regarding the treatment
of MS pain, RCTs must be conducted to evaluate the
efficacy and safety of existing treatments for neuropathic
and non-neuropathic pain in patients with MS, includ-
ing antidepressants, anticonvulsants, opioid analgesics,
and non-steroidal anti-inflammatory drugs [8], as well
as non-pharmacologic therapies [97].
Few studi es have examined the effects of disease-
modifying therapy on pain in MS patients, not only in
alleviating pain but also as a source of pain. Because
such therapy has become the standard of care for relaps-
ing MS, research evaluating its effects on pain, including
the possibility of preventing such pain, should be a high
priority for future clinical trials. This information is
likely to have important implications in determining
the risk-benefit ratio for patients and clinicians and the
cost-effectiveness of treatments for policy-makers and
third party payers.
5. Disclosure
ABO has received research support from Endo and
the Mayday Fund, and is the recipient of an institutional
career development award (T32 AG020493 -02) from the
United States National Institutes of Health. SRS has
received research support, consulting fees, or honoraria
in the past year from Acorda, Berlex, Biogen, Forest,
Genentech, National Multiple Sclerosis Soc iety, Novar-
tis, Pfizer, Serono, Teva, and US National Institutes of
Health. DNH has received research support in the past
year from Astellas and the US National Institutes of
Health. JDM has received consulting fees or honoraria
in the past year from Biogen and Pfizer. RHD has
received research support, consulting fees, or honoraria
in the past year from Allergan, Balboa, CombinatoRx,
Dara, Eli Lilly, Endo, EpiCept, Fralex, GlaxoSmithK-
line, GW Pharmaceuticals, KAI Pharmaceuticals,
Merck, NeurogesX (also stock options), Pfizer, Super-
nus, US Food and Drug Administration, US National
Institute of Health, US Veterans Administration,
Wyeth, and XTL Biopharmaceuticals.
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Appendix A
Summary of prevalence studies, emphasizing those with prospective research designs, patients with definite MS, and clear definitions of pain and the time
frame during which pain occurred
Study Year Prospective/
retrospective
MS diagnosis Pain
definition
clear?
Pain time
frame
Location Patient
population
Number
of patients
Important
exclusions
Controls
General pain prevalence
Studies meeting all criteria
Vermote 1986 Prospective Definite Yes Now Belgium Rehabilitation 83 HA, visceral
pain
None
Stenager 1991 Prospective Definite Yes Now, MS
onset, during
MS
Denmark Hospitalized 117 HA, minor
pain relieved
by analgesics
None
Archibald 1994 Prospective Definite Yes Month Canada Clinic 85 None None
Indaco 1994 Prospective Definite Yes MS onset &
during MS
Italy Clinic 122 HA, chronic
pain syndromes
relieved
by analgesics
None
Stenager
a
1995 Prospective Definite Yes Now Denmark Subset of
Stenager 1991
49 HA, minor
pain relieved
by analgesics,
age < 25 or > 45
None
Svendsen 2003 Prospective Definite Yes Month Denmark MS registry 627 None Age/sex-
matched
non-MS
Beiske 2004 Prospective Definite Yes Month Norway Clinic 142 HA None
Solaro 2004 Prospective Definite Yes Now Italy Clinic 1672 HA, ON,
somatic pain
other than
back pain
None
Kalia 2005 Prospective Definite Yes Month &
MS onset
Canada Clinic 99 Chronic pain
due to
concomitant
disease or
trauma
Historical,
age/sex
adjusted
Osterberg 2005 Prospective Definite Yes During MS Sweden Clinic 364 HA None
Not definite MS
Ehde 2003 Prospective NR Yes 3 months USA MS registry 442 None None
12 A.B. O’Connor et al. / Pain xxx (2007) xxx–xxx
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Page 12
Ehde 2006 Prospective NR Yes 3 months USA MS registry 180 ‘‘Occasional
headaches or
menstrual
cramps’’
None
Hadjimichael 2007 Prospective NR Yes 1 month North
America
MS registry 15853 None Survey non-
reponders
Retrospective
Buchanan 2002 Retrospective NR Yes Week USA SNF admits 14009 None SNF patients
Buchanan
a
2003 Retrospective NR Yes Week USA SNF admits NR None SNF patients
Newland 2005 Retrospective NR Yes Week USA SNF admits 247 None SNF patients
Unclear pain definition
Albert 1969 NR NR No NR USA Clinic 35 NR None
Clifford 1984 Retrospective Probable to
definite
No NR USA Clinic 317 HA, traumatic
pain, minor pain
relieved by
analgesics
None
Kassirer 1987 Prospective Definite No Unclear USA Clinic 28 Non-veterans None
Moulin 1988 Prospective Probable to
definite
No During
disease
Canada Clinic 159 HA, minor pain
relieved by
analgesics,
institutionalized
None
Warnell 1991 Prospective Possible to
definite
No NR Canada Clinic 364 Institutionalized None
Goodin 1999 Prospective Definite No NR USA MS registry 168 None None
Nortvedt 1999 Prospective Probable to
definite
No Month Norway Clinic 194 None Historical,
age/sex
adjusted
Rae-Grant 1999 Prospective NR No Unclear USA MS registry 224 None Age/sex-
matched
non-MS
Specific pain conditions
Trigeminal neuralgia
Rushton 1965 Retrospective NR Yes 15 Years USA Clinic 3880 None None
Chakravorty 1966 Retrospective NR No 14 Years India NR 10 None None
Jensen 1982 Retrospective NR Yes 33 Years Denmark NR 22 None None
Katusic 1990 Retrospective NR Yes 20 Years USA Clinic 3 None None
Hooge 1995 Retrospective Definite Yes 13 Years Canada Clinic 1882 None None
Eriksson 2002 Retrospective Probable to
definite
No NR Sweden Clinic 255 None None
A.B. O’Connor et al. / Pain xxx (2007) xxx–xxx 13
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Headache
Watkins 1969 Prospective Definite Yes NR England Hospitalized 100 None Healthy
Rolak 1990 Prospective Definite Yes NR USA Clinic 104 Trigeminal
neuralgia, ON
(1) Suspected
MS, (2) age/
sex/disability-
matched
non-MS
Po
¨
llmann 2002 Prospective Definite Yes Onset, 1,3,6
months
Germany Clinic 65 None None
Lhermitte’s sign
Kanchandani 1982 Prospective Definite Yes Ever England Hospitalized
and clinic
69 None None
Al-Araji 2005 Prospective Definite No Unclear Canada Clinic 300 None Healthy
NR, not reported; HA, headache; ON, optic neuritis; ‘‘Now,’’ at the time of assessment; SNF, skilled nursing facility.
a
Excluded from analysis because it represents a reanalysis of a previously published patient sample.
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    • "Pain is an important component of MS, which, despite its significant impact on patients' QoL, is often neglected or undertreated. Patients with MS present not only spontaneous pain, but also several forms of evoked pain such as cutaneous mechanical pain and cold hypersensitivity at the distal extrem- ities [41, 42]. Promising results in the treatment of pain have been reported for PEA in various clinical trials. "
    [Show abstract] [Hide abstract] ABSTRACT: Palmitoylethanolamide (PEA) is an endogenous lipid mediator known to reduce pain and inflammation. However, only limited clinical studies have evaluated the effects of PEA in neuroinflammatory and neurodegenerative diseases. Multiple sclerosis (MS) is a chronic autoimmune and inflammatory disease of the central nervous system. Although subcutaneous administration of interferon (IFN)-β1a is approved as first-line therapy for the treatment of relapsing-remitting MS (RR-MS), its commonly reported adverse events (AEs) such as pain, myalgia, and erythema at the injection site, deeply affect the quality of life (QoL) of patients with MS. In this randomized, double-blind, placebo-controlled study, we tested the effect of ultramicronized PEA (um-PEA) added to IFN-β1a in the treatment of clinically defined RR-MS. The primary objectives were to estimate whether, with um-PEA treatment, patients with MS perceived an improvement in pain and a decrease of the erythema width at the IFN-β1a injection site in addition to an improvement in their QoL. The secondary objectives were to evaluate the effects of um-PEA on circulating interferon-γ, tumor necrosis factor-α, and interleukin-17 serum levels, N-acylethanolamine plasma levels, Expanded Disability Status Scale (EDSS) progression, and safety and tolerability after 1 year of treatment. Patients with MS receiving um-PEA perceived an improvement in pain sensation without a reduction of the erythema at the injection site. A significant improvement in QoL was observed. No significant difference was reported in EDSS score, and um-PEA was well tolerated. We found a significant increase of palmitoylethanolamide, anandamide and oleoylethanolamide plasma levels, and a significant reduction of interferon-γ, tumor necrosis factor-α, and interleukin-17 serum profile compared with the placebo group. Our results suggest that um-PEA may be considered as an appropriate add-on therapy for the treatment of IFN-β1a-related adverse effects in RR-MS.
    No preview · Article · Feb 2016 · Neurotherapeutics
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    • "A progressive form and altered visual function at EDSS score increased the risk of low back pain. Patients with a progressive form are more at risk than others to have neuropathic or nociceptive pains [9]. Visual dysfunction is common in patients with MS [27]. "
    Full-text · Article · Jan 2016
    • "MS-associated pain is typically classified as either neuropathic or non-neuropathic in origin [2]. Between 5% and 32% of pwMS regard pain as their most severe symptom [2] . Current biomedical treatments demonstrate limited efficacy [3] and many pwMS experience uncontrollable pain [4]. "
    [Show abstract] [Hide abstract] ABSTRACT: Pain affects around two-thirds of people with Multiple Sclerosis (pwMS). Biomedical treatments show limited efficacy. A recently developed cognitive-behavioural model of Multiple Sclerosis (MS) pain suggests several psychosocial factors may worsen pain and related disability. The current study investigated whether psychosocial factors drawn from this model explain significant amounts of the variance in pain severity and interference over and above measures of disease severity and pain subtype. Six hundred and twelve pwMS experiencing pain completed a UK wide cross-sectional survey including valid and reliable psychometric questionnaires. Hierarchical regressions determined the relative contribution of disease severity and psychosocial factors to predicting pain severity and interference. All psychosocial factors including distress, negative beliefs about pain and its consequences, and avoidance of activity, were related to pain outcomes, explaining a further 24% and 30% of the variance in pain severity and interference after controlling for demographic and disease variables. Findings were similar for neuropathic and non-neuropathic pain subgroups. All pwMS reported significant pain and associated disability even though over 90% were taking pain medication. Psychosocial factors identified as important in predicting pain severity and, to a greater extent, pain interference are potentially modifiable and may be important treatment targets for both pain subtypes. © 2015 EAN.
    No preview · Article · Jul 2015 · European Journal of Neurology
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