pain is a common and disabling symptom in persons with multiple sclerosis ( ms ) , with a prevalence ranging widely between 29% and 86% [ 13 ] .
several different pain conditions are associated with ms and may be defined by location , by presumed mechanism , and by duration , ranging from paroxysmal to chronic . restricting our focus to chronic pain , approximately 75% of ms patients
one broad category of ms - related pain is central neuropathic pain , which includes dysesthetic extremity pain , a chronic form of pain described as the most common .
other chronic pain conditions are musculoskeletal pain ( e.g. , back pain ) , painful tonic spasms , and headache .
fibromyalgia ( fm ) , originally described as a psychogenic disorder or a variant of depression , has recently been considered a model of central neuropathic pain .
neurophysiologic methods able to explore the nociceptive afferent system suggest that in fm patients weak painful stimuli delivered at both tender and non - tender points induce cortical hyperactivation and lead to generalized hyperalgesia .
these phenomena have been confirmed by functional magnetic resonance imaging , whose findings showed a significantly greater activation in the anterior insula and the cingulate cortex in response to painful stimuli in fm patients compared to controls . a study investigating the intensity - dependence of auditory - evoked cortical potentials found that fm patients are hypervigilant to acoustic stimuli and showed a reduced inhibition response to noxious and intense auditory stimuli .
this pattern of  cortical hypervigilance  to multimodal stimuli is well known in fm patients [ 810 ] .
therefore , on the basis of both neurophysiological and functional magnetic resonance imaging methods , it has been supposed that fm is related to cns malfunction and altered pain transmission and perception , as supported by the augmented stimulus responses transmitted by primary afferent fibers , the impairment of descending inhibitory pain pathways , and the altered release of neurotransmitters involved in pain modulation .
fm may appear alone , with a prevalence of 2.94.7% in the general population , or associated with other rheumatic diseases , such as up to 25.3% in systemic lupus erythematosus ( sle ) and up to 19.8% in rheumatoid arthritis ( ra ) .
the prevalence of fm among ms patients and its impact on health - related quality of life ( hrqol ) has not yet been clearly determined .
the few studies available on this topic exclusively collected data from administrative records or self - reported questionnaires . however , fm was the only co - morbidity analyzed in ms that was proved to exert a moderate impact on physical hrqol , being generally milder than the effect of other diseases . in our own experience ,
we have observed a high incidence of fm associated with ms , as ascribable to various factors .
first , some of the pathophysiological abnormalities of each of these disorders may be shared . a previous study by our group , which evaluated the thermal and discomfort thresholds in ms patients , yielded lower values in patients than in healthy controls .
similarly , fm is characterized by central sensitization , which is a disordered sensory processing in the central nervous system and is responsible for an increased perception of pain in response to low stimuli of different types .
, fm may result from a cervical myelopathy due to various causes , such as a motor vehicle accident , surgery , arnold - chiari malformation , spinal canal stenosis , positional cervical compression , or trauma .
third , some of the predisposing risk factors to these 2 diseases , such as female sex , may be shared . for all these reasons
, we believe that the frequency of fm in ms patients is higher than in the general population and similar to that observed in other rheumatic diseases .
the primary aim of this study was to evaluate the frequency of fm in a continuous series of italian ms patients by means of specific validated diagnostic criteria , regardless of the various types of chronic pain referred .
the secondary aim of the study was to detect any demographic and clinical characteristics associated with fm in ms .
moreover , when associated with a highly disabling disease , such as ms , it clearly exacerbates the patients already compromised quality of life .
the third objective of this study was to evaluate the possible impact of fm on ms patients hrqol , regardless of the other types of chronic pain .
we recruited , between october 2012 and august 2013 , a continuous series of patients with definite ms according to the mcdonald criteria , from a total of 205 in- and out - patients undergoing rehabilitation for ms at the santa lucia foundation , a large , free - standing , university - affiliated rehabilitation institute not dependent on an acute - care general hospital .
the exclusion criteria were age < 18 years , other known neurological or rheumatic diseases , other disorders of the spine , cancer , renal diseases , diabetes mellitus , severe psychiatric diseases , relapses within 1 month prior to enrollment , and a mini - mental state examination score < 23 .
the study was approved by the ethics committee of our foundation and informed consent was given in writing by all the patients .
all the patients underwent a structured interview to collect their clinical history , as well as ms preventive treatment intake .
a neurological examination was performed by means of the kurtzke expanded disability status scale ( edss ) , with its functional systems .
the presence of chronic pain , which had been constant or nearly constant in the previous month , was investigated at the time of evaluation .
the referred pain was further rated as neuropathic or not according to the dn4 questionnaire , consisting of both sensory descriptors and signs related to bedside sensory examination , and providing very good sensitivity ( 83% ) and specificity ( 90% ) for identification of chronic pain associated with a lesion in either the peripheral or central nervous system ; a score of at least 4 out 10 is suggestive for neuropathic pain .
the patients with a score < 4 were diagnosed with musculoskeletal pain to simplify the classification , even if it may include pain of mixed type caused by the complex interplay of nociceptive , neuropathic , and pathogenic mechanisms .
depression was assessed by means of the beck depression inventory ii ( bdi  ii ) .
the cut - off scores used were : 013 : minimal depression ; 1419 : mild depression ; 2028 : moderate depression ; and 2963 : severe depression . a deep rheumatologic examination , as well as a wide panel of auto - antibodies , was performed by a ward rheumatologist to exclude any co - morbidity with other rheumatic diseases . to investigate the fm co - morbidity ,
all the patients were assessed according to the 1990 american college of rheumatology ( acr ) diagnostic criteria .
for a diagnosis of fm to be made , the 1990 acr diagnostic criteria require tenderness on pressure ( tender points ) in at least 11/18 specified sites , as well as the presence of widespread pain for at least 3 months .
hrqol was assessed by means of the medical outcome 36-item short form health survey ( sf-36 ) , which analyzes physical and mental health status ( phs and mhs , respectively ) .
the item scores range from 0 ( poor health ) to 100 ( optimal health ) .
according to published reports , the frequency of fm is approximately 19.8% in ra and 3.8% in the general population . for this pilot study ,
a sample size of at least 75 patients would provide 80% power for detecting a difference in fm frequency not below 16% between the ms group and the general population , at the 5% level of significance .
both the epidemiological and clinical characteristics of the patients enrolled were summarized by mean and standard deviation for numerical variables , and by frequencies and percentages for categorical variables .
the shapiro - wilk test was used to check the normality distribution for each variable used in the study .
a p<0.05 was sufficient to reject the null hypothesis that the variable was normally distributed .
patients were divided into 3 sub - groups ( 1 without pain , 1 with pain not fm - type , and 1 with pain fm - type ) according to the modified acr 1990 criteria .
the statistical analysis between the 2 groups was performed by means of the mann - whitney rank sum test or the chi - square test , as appropriate .
the nonparametric kruskal - wallis one - way analysis of variance followed by the dunn s post test was performed to compare more than 2 unmatched sub - groups .
we recruited , between october 2012 and august 2013 , a continuous series of patients with definite ms according to the mcdonald criteria , from a total of 205 in- and out - patients undergoing rehabilitation for ms at the santa lucia foundation , a large , free - standing , university - affiliated rehabilitation institute not dependent on an acute - care general hospital .
the exclusion criteria were age < 18 years , other known neurological or rheumatic diseases , other disorders of the spine , cancer , renal diseases , diabetes mellitus , severe psychiatric diseases , relapses within 1 month prior to enrollment , and a mini - mental state examination score < 23 .
the study was approved by the ethics committee of our foundation and informed consent was given in writing by all the patients .
all the patients underwent a structured interview to collect their clinical history , as well as ms preventive treatment intake .
a neurological examination was performed by means of the kurtzke expanded disability status scale ( edss ) , with its functional systems .
the presence of chronic pain , which had been constant or nearly constant in the previous month , was investigated at the time of evaluation .
the referred pain was further rated as neuropathic or not according to the dn4 questionnaire , consisting of both sensory descriptors and signs related to bedside sensory examination , and providing very good sensitivity ( 83% ) and specificity ( 90% ) for identification of chronic pain associated with a lesion in either the peripheral or central nervous system ; a score of at least 4 out 10 is suggestive for neuropathic pain .
the patients with a score < 4 were diagnosed with musculoskeletal pain to simplify the classification , even if it may include pain of mixed type caused by the complex interplay of nociceptive , neuropathic , and pathogenic mechanisms .
depression was assessed by means of the beck depression inventory ii ( bdi  ii ) .
the cut - off scores used were : 013 : minimal depression ; 1419 : mild depression ; 2028 : moderate depression ; and 2963 : severe depression . a deep rheumatologic examination , as well as a wide panel of auto - antibodies , was performed by a ward rheumatologist to exclude any co - morbidity with other rheumatic diseases . to investigate the fm co - morbidity ,
all the patients were assessed according to the 1990 american college of rheumatology ( acr ) diagnostic criteria .
for a diagnosis of fm to be made , the 1990 acr diagnostic criteria require tenderness on pressure ( tender points ) in at least 11/18 specified sites , as well as the presence of widespread pain for at least 3 months .
hrqol was assessed by means of the medical outcome 36-item short form health survey ( sf-36 ) , which analyzes physical and mental health status ( phs and mhs , respectively ) .
the item scores range from 0 ( poor health ) to 100 ( optimal health ) .
according to published reports , the frequency of fm is approximately 19.8% in ra and 3.8% in the general population . for this pilot study ,
a sample size of at least 75 patients would provide 80% power for detecting a difference in fm frequency not below 16% between the ms group and the general population , at the 5% level of significance .
both the epidemiological and clinical characteristics of the patients enrolled were summarized by mean and standard deviation for numerical variables , and by frequencies and percentages for categorical variables .
the shapiro - wilk test was used to check the normality distribution for each variable used in the study .
a p<0.05 was sufficient to reject the null hypothesis that the variable was normally distributed .
patients were divided into 3 sub - groups ( 1 without pain , 1 with pain not fm - type , and 1 with pain fm - type ) according to the modified acr 1990 criteria .
the statistical analysis between the 2 groups was performed by means of the mann - whitney rank sum test or the chi - square test , as appropriate .
the nonparametric kruskal - wallis one - way analysis of variance followed by the dunn s post test was performed to compare more than 2 unmatched sub - groups .
from october 2012 to august 2013 , 205 ms in- and out - patients were admitted at our hospital .
out of them , 72 ( 35.1% ) fulfilled the exclusion criteria , such as diabetes mellitus ( 4.8% ) , relapses in the last month prior to enrollment ( 3.9% ) , cancer ( 2.4% ) , age < 18 years ( 0.9% ) , disorders of the spine ( 5.8% ) , other rheumatic disease ( 7.3% ) , patients with acute or occasional pain ( 6% ) , as well as severe cognitive impairment ( 9.7% ) , and were excluded .
the remaining 133/205 ( 64.8% ) ms patients were enrolled in the study ; the patients demographic and clinical characteristics are shown in table 1 .
the f / m ratio was 1.8 , which is in keeping with previous reports .
the patients enrolled had a mean age of 51.812.9 years , a high disability ( mean edss 5.52.6 ) and mean disease duration of 19.311.7 years .
most of the patients ( 67.7% ) were in the secondary progressive phase of disease .
all the patients enrolled were investigated for the occurrence of chronic pain , which was referred by 88/133 ( 66.2% ) and absent in the remaining 45/133 ( 33.8% ) ( patients with no pain [ nop ] ) ( table 1 ) . according to the dn4 questionnaire , the pain was neuropathic in 12/88 ( 13.7% ) patients and musculoskeletal or mixed in 76/88 ( 86.3% ) patients .
the demographic and clinical characteristics of these sub - groups did not differ significantly ( table 2 ) .
among all the patients enrolled , 23/133 ( 17.3% ) also fulfilled the 1990 acr criteria for fm ( pfm+ patients ) ; out of them , 5 ( 21.7% ) had neuropathic pain , while in the remaining 18 ( 78.3% ) the pain was musculoskeletal ( p=0.03 ) , as determined by the dn4 questionnaire .
these 2 pfm+ subgroups did not differ in any demographic and clinical characteristics , and were grouped together for further statistical analysis ( table 3 ) .
the other 65/133 ( 48.9% ) ms patients with chronic pain , not fulfilling the 1990 acr criteria for fm , were considered to have chronic pain not fm type ( pfm patients ) .
out of them , 7 ( 10.8% ) had neuropathic pain and 58 ( 89.2% ) had musculoskeletal pain ( p=0.01 ) , as determined by means of the dn4 questionnaire .
these 2 pfm subgroups did not differ in any demographic and clinical characteristics , and were grouped together for further statistical analysis ( table 4 ) .
the distribution of our sm patients in the 3 sub - groups ( nop , pfm+ and pfm ) is shown in figure 1 .
the frequency of neuropathic and musculoskeletal pain did not differ between the pfm+ and pfm sub - groups ( p=0.18 ) the pfm+ patients were predominantly female ( p=0.03 ) and had a greater edss than the nop group ( p=0.01 ) , but not greater than the pfm patients ; no significant differences among pfm+ , pfm , and nop groups emerged as regards the other demographic and clinical characteristics ( table 5 ) .
depression was present in 54.1% of the patients enrolled , generally displaying a mild depression ( mean dbi - ii 17.0111.7 ) .
out of the patients with chronic pain , 42 ( 66.7% ) were diagnosed with depression , compared to 11 ( 31.4% ) patients in the nop group , by means of the dbi - ii ( p=0.007 ) . when the subgroups were considered separately , the pfm+ patients had a more pronounced depression than the nop group ( p=0.002 ) , mainly ranging in the moderate / severe grade ( p=0.01 ) , but did not differ from the pfm patients ( table 6 ) .
fatigue , as assessed by means of the fss , was present in 102/133 ( 76.7% ) of our sample , but did not differ among the 3 sub - groups ( table 6 ) .
the pfm+ patients scored the worst in both the phs and the mhs when compared to the pfm and the nop groups ( p<0.01 ) .
the prevalence of chronic pain in ms is estimated at 5379% in studies based on mailed survey , in - person survey , or in - person assessment , and evaluating the prevalence of pain during the month prior to assessment [ 3335 ] . despite the slightly different values reported in the literature , it may vary because of the heterogeneous methods and definition of pain adopted , the 66.2% prevalence of chronic pain we found in our sample may be considered in keeping with the literature .
this frequency is higher than the 3.8% reported in the general population , and similar to those reported in other rheumatic diseases , such as ra and sle .
few studies have investigated the co - morbidity of fm in ms . the fm prevalence in one such study , which investigated different types of chronic pain and
was based on administrative claim records , was 14.06% in the ms cohort . in another study , which investigated various co -
morbidities by means of a self - reported validated questionnaire in an american ms population , fm was reported by 4.9% of the patients .
it is known that the validity of self - reported diagnoses varies depending on the co - morbidity investigated .
indeed , it is very accurate for common disorders such as hypertension and diabetes , but is less accurate for uncommon disorders such as arthritis and fm . in our study ,
a ward rheumatologist performed an examination to assess the presence of co - morbid fm in our ms patients , and the differences in the diagnostic methods adopted may explain the high frequency of fm detected in our ms sample . of the patients with chronic pain ,
only 13.7% had a neuropathic pain , without significant difference between the pfm+ and pfm sub - groups .
this frequency is low if compared with other data on neuropathic pain derived from systematic review and meta - analysis , which estimate a prevalence of 28.5% in ms .
we identified some methodological variables in the studies included , such as deficient blinding , different study design , and varying diagnostic criteria . in our study
we focused on pain lasting for no less than 1 month , excluding forms of acute and paroxysmal pain , and used the dn4 questionnaire .
these 2 factors may justify the low prevalence of neuropathic pain found in our sample .
when considering the pfm+ subgroup , we found a higher prevalence of females with respect to the nop sub - group only .
female sex appears to play a critical role in the development of ms , and women are diagnosed as having fm approximately 7 times more often than men .
the fact that female sex appears to be a major risk factor for the development of both ms and fm may , at least in part , explain this co - morbidity .
moreover , women are about 2 times more likely to report chronic and widespread pain , because of higher pain sensitivity , and this may explain the lack of difference between the 2 different sub - groups of ms patients with chronic pain ( pfm+ and pfm ) .
the other difference between pfm+ and nop patients was a higher degree of disability in the former , although the edss was high in both groups .
this finding seems to suggest that pain may have a negative effect on disability and is in line with those reported in the literature .
the impact of pain on disability was found to be modest in patients with a low edss   and high in those with a high edss .
the association between pain and disability may be inter - related , with these 2 factors exacerbating each other , especially in patients with a higher degree of impairment .
our data confirm the high prevalence of depression in ms , which is estimated at around 50% .
in addition , we found a more pronounced depression in pfm+ patients than in nop patients , but similar to the pfm patients .
this finding seems to show a negative impact of fm , but not of other types of chronic pain , on patient mood .
findings from studies that examined the relationship between pain and depression in ms are mixed , with roughly equal numbers of studies showing a positive versus a null relationship [ 4548 ] . instead , the high rate of co - morbidity between fm and depression is well known .
moreover , fm and depression share a similar pathophysiology , with a more pronounced deficit in pain inhibition in fm patients with depressive symptoms . in our study ,
fatigue was detected in 75% of the patients , which is in keeping with reports in the literature , with no difference between the 3 sub - groups . however , fatigue is also very frequent in fm , with figures ranging between 78% and 94% .
fatigue in both fm and ms may arise from a range of mechanisms that have yet to be fully clarified , and the complexity of its pathophysiology may thus explain why we could not find any associations with the presence of chronic pain or fm
. the impact of fm on family , social , and professional life is well known .
patients with fm were found to have a worse qol even than ra patients   and ms has a significant impact on health - related qol at all stages of disease .
thus , the co - morbidity of fm in ms clearly exacerbates the already compromised qol . in our sample ,
the pfm+ group scored the worst in both phs and mhs , which points to a marked effect of fm co - morbidity on ms patient qol .
our findings are consistent with those of previous studies , which have shown that , out of various co - morbidities , fm has a relevant impact on physical and mental hrqol in ms patients .
in our series we found a prevalence of 66.2% of chronic pain , with those patients displaying mainly musculoskeletal - type pain , greater disability , and more severe depression . in our sample , almost 1/5 of ms patients had a co - morbidity with fm , which is a significantly higher prevalence than that observed in the general population , but similar to those reported in sle and ra . even if pfm+ patients were similar to pfm patients , according to the clinical and demographic characteristics , fm occurrence was associated with a stronger impact on patient qol .
fm co - morbidity should be further investigated in ms patients , given its frequency and impact on patient quality of life .
one limitation of this study is the lack of a wider range of edss scores .
indeed , a larger study , including patients with lower edss scores , might shed more light on how frequent fm is , even in the early stage of disease .
 backgroundchronic pain is common in persons with multiple sclerosis ( ms ) , but the co - morbidity of fibromyalgia ( fm ) has yet to be investigated in ms . 
 objectives of the study were to evaluate , among the various types of chronic pain , the frequency of fm in ms and its impact on ms patients health - related quality of life ( hrqol).material / methods133 ms patients were investigated for the presence and characterization of chronic pain within 1 month of assessment . a rheumatologist assessed the presence fm according to the 1990 acr diagnostic criteria . 
 depression , fatigue , and hrqol were also assessed by means of specific scales.resultschronic pain was present in 66.2% of patients ( musculoskeletal in 86.3% ; neuropathic in 13.7% ; absent in 33.8% [ called nop ] ) . 
 pain was diagnosed with fm ( pfm+ ) in 17.3% of our ms patients , while 48.9% of them had chronic pain not fm type ( pfm ) ; the prevalence of neuropathic pain in these 2 sub - groups was the same . 
 pfm+ patients were prevalently females and had a higher edss than nop . 
 the pfm+ patients had a more pronounced depression than in the nop group , and scored the worst in both physical and mental qol.conclusionsin our sample of ms patients we found a high prevalence of chronic pain , with those patients displaying a higher disability and a more severe depression . 
 moreover , fm frequency , significantly higher than that observed in the general population , was detected among the ms patients with chronic pain . 
 fm occurrence was associated with a stronger impact on patients qol . 
Background
Material and Methods
Patient selection and evaluations
Statistical analysis
Results
Discussion
Conclusions