Pain is frequently reported by people with multiple sclerosis (MS). It has been
associated with decreased quality of life, psychiatric morbidity, interference with day
to day activities, and frequent healthcare attendance. It has been reported by people
with multiple sclerosis to be one of their most important symptoms, and available
treatments are limited in their effectiveness.
Despite this, our understanding of the epidemiology and mechanisms of pain in
people with MS are limited.
Our understanding of the interactions of central nervous system mechanisms and
pain states overall is growing. However, the application of this knowledge to MS is
incomplete. Previous studies have shown that the descending pain modulatory
system (DPMS) is an endogenous network of cortical and subcortical brain structures
which act to limit, or accentuate, an individual’s perception of pain, via descending
brainstem pathways. Associated clinical measures include depression, anxiety, and
cognitive flexibility. Our understanding of the function or dysfunction of this system
in MS is limited. We do not know if the MS disease process may adversely affect the
structure or function of the DPMS.
In people with neuropathic limb pain in relapsing remitting MS (RRMS), compared
to people with RRMS who do not have pain, there will be disruption of the
endogenous descending pain modulatory system. This will manifest as impaired
descending inhibition of pain.
Aims and Methods
Establishing the background using systematic reviews:
The first aim of this thesis was to establish the prevalence, natural history and
associations of pain (and pain syndromes) occurring in people with MS.
The second aim was to explore existing knowledge of how the MS disease process
may contribute to pain states, using a systematic review of neuroimaging studies.
Prospective clinical study:
A case-control study of 47 people with RRMS was then carried out. 31 of these had
neuropathic pain in the limbs, and 16 did not have pain. Using targeted assessments,
function of the descending pain modulatory system was assessed in the following
First: Detailed clinical, behavioural and neuropsychological assessment, focussing on
cognitive, behavioural and affective features known to be closely related to the
Second: MRI imaging of brain structure, focussing on the volume and location of
MS lesions, as well as the volume of key grey-matter structures involved in the
Third: Resting state functional MRI imaging of the brain, focussing on functional
connectivity between the rostral anterior cingulate cortex and two other key DPMS
structures (dorsolateral prefrontal cortex, and periaqueductal gray).
Meta-analysis of existing prospective studies confirmed that pain is very common in
MS, affecting about 63% of people with MS on average (95%CI between 55 and
70%). Many different types of pain contribute to this overall estimate. No significant
associations with disease course or stage emerged.
Several neuroimaging studies have assessed people with MS-associated pain using
MRI. These studies were often small, and with associated methodological issues. It is
likely that location of MS lesions is implicated in aetiology of pain syndromes in
some cases, though our overall knowledge is limited.
In a prospective study, people with and without pain were matched for age and
gender. Furthermore, groups were balanced for a range of other variables. The pain
group more frequently received gabapentinoid medications.
The presence of pain was significantly associated with increased scores for
depression, fatigue and catastrophising, as well as with specific impairments at
neuropsychological assessment, including cognitive flexibility. Many of these
impairments are directly relevant to existing models of the DPMS.
Overall volume of MS lesions was not different in people with pain, though lesions
were more likely to occur in the brainstem. Some alterations of grey-matter volumes
in people with pain which mirrored studies of pain disorders outside MS were found,
but these did not involve structures key to the DPMS. Affected structures included
trigeminothalamic nucleus (relative volume increase in pain group), posterior
cingulate cortex and parahippocampal gyrus (volume decrease in pain group).
Functional connectivity of the rostral anterior cingulate cortex to the periaqueductal
grey matter, a key structure in the descending modulation of pain, was stronger in the
group without pain. Conversely, functional connectivity to the dorsolateral prefrontal
cortex, repeatedly implicated in the DPMS and thought to be involved in cognitive
evaluation and flexibility, was stronger in the pain group. MS lesion volume
appeared to account for some of this difference in a multivariate analysis.
Key limitations of this work include cross-sectional design, small sample size, and
number of statistical comparisons carried out.
Systematic reviews examined the prevalence, natural history and associations of pain
in MS, as well as examining existing neuroimaging studies which investigated how
the MS disease process could contribute to pain states.
A prospective study found evidence of both emotional/affective and cognitive
dysfunctions relevant to the hypothesis of dysfunction in the DPMS.
Higher likelihood of MS lesions in the brainstem could be relevant to DPMS
function. Separately, there were structural grey-matter volume alterations reflecting
those found in many pain studies outside MS. Importantly, however, these did not
affect key DPMS structures.
Resting state functional MRI however demonstrated altered connectivity of core
DPMS structures, which may be partly mediated by MS lesion volume. Functional
connectivity findings could be consistent with the hypothesis of impaired descending
pain inhibition, in people with relapsing remitting MS affected by neuropathic limb
|dc.relation.hasversion||P Foley, H Vesterinen, B Laird, E Sena, L Colvin, S Chandran, M MacLeod, M Fallon, “Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis” Pain, Volume 154 (5), 2013, p632-642||en
|dc.relation.hasversion||D Seixas, P Foley, J Palace, D Lima, I Ramos, I Tracey, “Pain in multiple sclerosis: A systematic review of neuroimaging studies”, NeuroImage: Clinical Volume 5, 2014, p322-331 (166)||en