The Prevalence of Pain in Adults with Multiple Sclerosis: A Multicenter Cross-Sectional Survey

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1 Pain Medicine 2015; 16: Wiley Periodicals, Inc. The Prevalence of Pain in Adults with Multiple Sclerosis: A Multicenter Cross-Sectional Survey Jelena Drulovic, MD, PhD,* Vanja Basic-Kes MD, PhD, Sanja Grgic, MD, PhD, Slobodan Vojinovic, MD, PhD, Evica Dincic, MD, PhD, Gordana Toncev, MD, PhD, Mira Gavric Kezic, MD, ** Darija Kisic-Tepavcevic MD, PhD, Irena Dujmovic, MD, PhD,* Sarlota Mesaros, MD, PhD,* Svetlana Miletic-Drakulic, MD, PhD, ** and Tatjana Pekmezovic, MD, PhD *Clinic of Neurology, Clinical Center of Serbia, Belgrade, Serbia; University Department of Neurology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia; Clinic of Neurology, Clinical Center Banja Luka, Banja Luka, Republic of Srpska-Bosnia and, Herzegovina; Clinic of Neurology, Clinical Center Nis, Nis, Serbia; Clinic of Neurology, Military Medical Academy, Belgrade, Serbia; ** Clinic of Neurology, Clinical Center Kragujevac, Kragujevac, Serbia; Department of Neurology, General hospital-uzice; Institute of Epidemiology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia Reprint requests to: Professor Jelena Drulovic, MD, PhD, Clinic of Neurology CCS, Dr Subotica 6, Belgrade 11000, Serbia. Tel: ; Fax: ; jelena60@eunet.rs. Dependent variable: presence of pain. Conflict of interest statement: The authors declare no financial or other conflict of interest in relation to this manuscript. Funding source: This work was supported by the Ministry of Education and Science of the Republic of Serbia (grants No and ). Abstract Objective. Examination of prevalence, intensity and associations of pain in persons with multiple sclerosis (MS). Design. Multicenter, international cross-sectional survey. Setting. Patients were recruited from seven MS centers: in Serbia (Clinic of Neurology, Clinical Center of Serbia, Belgrade; Clinic of Neurology, Military Medical Academy, Belgrade; Clinic of Neurology, Clinical Center Kragujevac; Clinic of Neurology, Clinical Center Nis; Department of Neurology, General Hospital-Uzice), in Republic of Srpska-Bosnia and Herzegovina (Clinic of Neurology, Clinical Center Banja Luka) and in Croatia (University Department of Neurology, Sestre Milosrdnice University Hospital Center, Zagreb). Subjects. Six hundred and fifty consecutive MS patients diagnosed according to the Revised McDonald criteria (2005), from the aforementioned centers, over the period of 6 months. Methods. A semistructured questionnaire was administered during a face-to-face interview with neurologists who also performed Expanded Disability Status Scale (EDSS), the Hamilton Rating Scale for Depression (HDRS) and Hamilton Rating Scale for Anxiety (HARS). To recognize predictive factors for the presence of pain, the linear regression analysis was used. Results. Lifetime prevalence of pain was 66.5% (point prevalence %). The prevalence of the comorbidity of pain and depression was 29.1%. Older age (P < 0.001), primary-progressive MS (P ), higher EDSS score (P ), higher scores of HDRS (P < 0.001), and HARS (P < 0.001) were significantly associated with pain. Finally, in our multivariate linear regression analysis, anxiety (P < 0.001) was the independent predictor of pain. 1597

2 Drulovic et al. Conclusions. We confirmed high prevalence of pain, affecting approximately more than half of patients during the course of MS. Pain in MS is associated with disability, depression and, especially with anxiety, which has significant implications for treatment. Key Words. Neurology; Pain Disorder Introduction Multiple sclerosis (MS) is an inflammatory and neurodegenerative chronic disease of the central nervous system (CNS). Pain is a common symptom in MS, which has been recently estimated to be experienced by 63% of patients [1]. Published pain prevalence in MS range widely because of significant differences in patients samples and study design [1 3]. Additionally, therefore the risk factors reported to be associated with greater likelihood of pain in adults with MS also differ in various studies [4]. Italian multicenter cross-sectional study as one of the largest epidemiological surveys, which included 1,672 MS patients, demonstrated that 43% of patients experienced pain and found that age, disease course, diseases duration and disability correlated with the presence of pain [2]. The WHO classifies pain as nociceptive, neuropathic and psychogenic [5]. Nociceptive pain is pain resulting from nociceptor activation by tissue-damaging stimuli. Neuropathic pain is a consequence of a lesion affecting the somatosensory system. According to classification proposed by O Connor et al., there are three main types of MS-related pain: neuropathic pain, musculoskeletal, nociceptive pain (i.e., painful tonic spasms, pain secondary to spasticity, pain related to being wheelchair bound), and headaches [4]. The aim of this multicenter, international cross-sectional survey was to characterize, using a structured questionnaire, the prevalence and clinical characteristics of pain in a cohort of well-defined MS patients. Material and Methods Study Participants Patients were recruited from seven MS centers: five in Serbia (Clinic of Neurology, Clinical Center of Serbia, Belgrade, Clinic of Neurology, Military Medical Academy, Belgrade, Clinic of Neurology, Clinical Center Kragujevac, Kragujevac, Clinic of Neurology, Clinical Center Nis, Nis, Department of Neurology, General hospital- Uzice), one in the Republic of Srpska-Bosnia and Herzegovina (Clinic of Neurology, Clinical Center Banja Luka, Banja Luka) and one in Croatia (University Department of Neurology, Sestre Milosrdnice University Hospital Center, Zagreb). A semistructured questionnaire was administered during a face-to-face interview with 650 MS patients, performed by previously trained examining neurologists. Included in the study were consecutive MS patients diagnosed according to the Revised McDonald criteria (2005) [6], diagnosed and followed in the above mentioned centers over the period of 6 months. Patients who had a relapse in the last month before the beginning of the study were excluded. This survey was approved by Institutional Review Boards in all centers. Measurements The questionnaire comprised age, gender, duration and course of the disease, Expanded Disability Status Scale (EDSS) [7], and type of pain including its therapy. Pain associated with MS was classified as neuropathic pain (continuous central neuropathic pain: neuropathic extremity pain; intermittent central neuropathic pain: Lhermitte s sign, trigeminal neuralgia), musculoskeletal, that is, nociceptive pain (low back pain and painful tonic spasms), and headache (mixed neuropathic and nonneuropathic pain) [4]. We considered pain symptoms at any point during the course of the patients disease and at the time of evaluation. Pain severity was assessed using mm numerical rating scale (Visual analog scale-vas) [8]. A higher score indicates greater pain intensity. The severity of depressive symptoms and anxiety were quantified in all patients using the Hamilton Rating Scale for Depression (HDRS) [9] and Hamilton Rating Scale for Anxiety (HARS) [10]. Both HDRS and HARS are clinicianadministered estimation scales that are conducted using a semistructured interview. The suggested cutoff values for HDRS are 0 9 (no depression), (mild depression), (mild to moderate depression), and >18 (moderate to severe depression) [9]. The total score of the HARS ranges from 0 to 56, in which value <17 indicates no or mild anxiety, values between 18 and 24 mild to moderate anxiety and values between 25 and 30 moderate to severe anxiety [10]. Statistical Analysis Descriptive statistics were computed to identify the point and lifetime prevalence of pain in MS patients. Patients characteristics for the pain and no pain groups were compared with Chi square and Kruskal Wallis tests for categorical and Mann Whitney test for not normally distributed continuous variables. Additionally, we used ANOVA for evaluating differences among normally distributed continuous variables. Spearman s correlation coefficients were used to determine the relationship between the presence of pain and both HDRS and HARS scores. To recognize predictive factors for the presence of pain among study participants, the univariate and multivariate linear regression analyses were performed. The SPSS 17.0 statistical software package (SPSS Inc., Chicago, IL, USA) was used to perform the statistical analysis. 1598

3 Prevalence of Pain in Multiple Sclerosis Table 1 Demographic and clinical characteristics for adults with multiple sclerosis according to the presence of pain. Number of patients Total (N 5 650) Patients with pain (N 5 432) Patients without pain (N 5 218) P-value Gender Male 188 (28.9%) 117 (27.1%) 71 (32.6%) Female 462 (71.1%) 315 (72.9%) 147 (67.4%) Age (years) * * * <0.001 Duration of the disease (years) * * * Clinical course: Relapsing-remitting 505 (77.7 %) 325 (75.2%) 180 (82.6%) Secondary progressive 100 (15.4 %) 72 (16.7%) 28 (12.8%) Primary progressive 45 (6.9 %) 35 (8.1%) 10 (4.6%) EDSS score** 3.0, , , HDRS score * * * <0.001 HARS score * * * <0.001 * Mean 6 SD. ** Expanded disability status scale. Median, Interquartile range. Results Demographic and clinical data from 650 patients with diagnosis of MS were collected by questionnaires in seven MS centers (Table 1). Questionnaires were divided into pain (432; 66.5%) and no pain (n 5 218; 33.5%) group. Patients with pain were significantly older, had a higher EDSS score and also higher both HDRS and HARS scores. The pain group comprised marginally significantly (P ) higher proportion of persons with SP and PP disease. According to the values of HDRS (scores > 9) 54.7% had depression (mild-17.9%; mild to moderate-12.9%; moderate to severe-23.9%). Out of 288 persons experiencing any pain at the time of evaluation, 189 (65.6%) met depression criteria (HDRS score > 9). The prevalence of the comorbidity of pain and depression is present in 29.1% of participants. HARS indicated no or mild anxiety in 79.9% patients, mild to moderate in 13.2%, and moderate to severe in 6.9%. There is significant correlation between presence of pain at the time of evaluation and both HDRS (q , P ) and HARS (q , P ). Different categories of prevalence in the total cohort of assessed MS patients are presented in Table 2. Lifetime prevalence of pain in the sample of 650 MS patients was 66.5%, while point prevalence was 44.3%. Additionally, we quantified prevalence of neuropathic extremity pain (52.9%), Lhermitte s sign (19.2%), trigeminal neuralgia (5.7%), low back pain (26.6%), painful tonic spasms (9.5%), and headache (39.5%). According to VAS scale, 35.6% of our 432 patients with pain described their pain intensity as mild, 37.6% as moderate, and 12.4% as severe. Out of 650 patients, 57.4% were taking pain medication during entire MS course: nonsteroid anti-inflammatory drugs-48.2%, trycyclic antidepressants-10.8%, antiepileptic medications-4.9%, and spasmolytics-9.5%. Univariate linear regression analyses (dependent variable: presence of pain) showed that older age (P < 0.001), primary-progressive course of MS (P ), higher EDSS score (P ), higher scores of HDRS (P < 0.001), and HARS (P < 0.001) were the significant predictors of pain in our MS patients (Table 3). Multivariate linear regression analysis revealed only age (standardized beta coefficient , P < 0.001) and anxiety, measured by HARS (standardized beta coefficient , P ) as independent predictors of pain in this study. Discussion This study assessed the prevalence of pain in large cohort of well-defined MS patients from several centers Table 2 Prevalence of pain symptoms in persons with multiple sclerosis (N 5 650) Prevalence of pain symptoms % Lifetime prevalence 66.5 Point prevalence 44.7 Type-specific prevalence Continuous central neuropathic pain 56.2 Intermittent central neuropathic pain 52.7 Musculoskeletal pain 49.7 Mixed neuropathic and non-neuropathic pain

4 Drulovic et al. Table 3 Univariate linear regression analyses of predictors of the presence of pain in persons with multiple sclerosis (N 5 650). Variable Standardized beta coefficient Age <0.001 Gender Duration of disease Primary-progressive MS EDSS score HDRS score <0.001 HARS score <0.001 in Serbia, Croatia and the Republic of Srpska-Bosnia and Herzegovina. Lifetime prevalence of pain in our sample of 650 MS patients was 66.5%, while point prevalence was 44.3%. This lifetime prevalence is in line with heterogeneous published prevalence of pain at any point during the course of the patients with MS which ranges widely from 34% to 92% [2,4,11 13]. Recently, a systematic review and meta-analysis showed an overall pain prevalence of 63% [1]. Several types of pain are associated with MS. Criteria used to define the various types of MS-related pain are different. It is essential to adequately define the various types of pain to better understand the underlying pathophysiological mechanisms and to consequently apply the proper treatment strategy. The prevalence of various types of pain varies among numerous studies. However, neuropathic pain and headaches are the most prevalent according to the published data [3]. Our results are in accordance with those findings, as most prevalent types of pain in our survey were also neuropathic extremity pain (52.9%) and headache (39.5%). Low back pain (26.6%) was also very common in our MS patients with prevalence very similar to that reported in above mentioned systematic review [3]. Prevalence of Lhermitte s sign (19.2%), trigeminal neuralgia (5.7%), and painful tonic spasms (9.5%) were also registered in our study. Recently, similarly, Osterberg et al. found trigeminal neuralgia in 4.9% of MS patients [12], although previous studies detected less frequent occurrence of trigeminal neuralgia in MS patients of 1 2% [2,14,15]. The pain severity in MS has been described in several studies. In most of them, the average pain intensity was estimated as moderate or mild [16,17]. Similarly, according to VAS scale, in our study majority of patients had mild or moderate pain, and only about 10% reported their pain as severe. To determine risk factors for pain in MS, several studies have compared MS patients with and without pain [4]. The results of those studies are rather inconsistent but in P the majority, the risk factors for development of pain in MS patients were older age, longer disease duration, and higher EDSS, as a measure of disease severity [2,16,18]. In our study, patients with pain were also significantly older than those without pain. Additionally, median EDSS, mean HDRS and HARS scores were significantly different between our patients with or without pain. Depression is a common and disabling symptom in MS, with a point prevalence ranging from 27 to 54% [19,20]. However, studies related to the prevalence of comorbidity of pain and depression are rather rare. Recently, Alschuler et al. emphasized that although, according to research from non-ms populations, pain and depression often co-occur and mutually impact each other, it is not clear whether the same phenomena are present for persons with MS [21]. The same authors reported that of persons experiencing any pain, 11 34% met depression criteria, and of persons meeting depression criteria, % reporting experiencing any pain [21]. Thus, they concluded, to our best knowledge in the first study reporting on the prevalence of this comorbidity, that this prevalence is 6 19%. Our results are in accordance with these previously published findings. We found the prevalence of the comorbidity of pain and depression in 29.1% of participants. Additionally, out of 288 persons experiencing any pain at the time of evaluation in our study, more than 65% met depression criteria. Regarding the difference in the comorbidity of pain and depression, in above mentioned studies, it should be mentioned that it has been previously published that comorbid pain and depression is suggested to exist in 27% of persons with neurologic conditions [22]. The significant correlations between presence of pain at the time of evaluation and both HDRS (P ) and HARS (P ) were registered. It should be emphasized that in three previously published cross-sectional studies with smaller cohorts of MS patients, association between pain and depression has been analyzed. Similar to our results, Grau- Lopez et al. found that pain was more frequent in MS patients with depression [23]. Conversely, pain was not found to be associated with depression in two remaining studies [24,25]. Finally, in our multivariate linear regression analysis, only HARS (P < 0.001) was the independent predictor of pain in MS patients. These findings are clinically relevant and warrant further study, especially related to the treatment. Appropriate approaches to treatment of pain in MS are not well defined yet. To optimize MS-related pain treatment, it is necessary to determine the origin of pain categories. Data related to treatment of pain in MS is very limited. In our study, about half of the patients were taking pain medication. Majority has taken nonsteroid antiinflammatory drugs, while trycyclic antidepressants, antiepileptic medications, and spasmolytics were used rarely. Several limitations of this study require to be mentioned. This study was cross-sectional; longitudinal study which 1600

5 Prevalence of Pain in Multiple Sclerosis could have followed the evolution of pain during disease would have been preferable. Additionally, it should be mentioned that possible presence of information bias could have meaningful implication in interpretation of our findings. Namely, the information regarding pain during the entire course of the disease may be wrong and consequently, possible disagreement of correct answers can arise due to memory bias. This type of bias can also occur in circumstances when patients with longer duration of MS become adapted to pain and thus might not be recognized this issue as relevant. Furthermore, investigators were not blinded, and finally there was no control group of patients without MS. Finally, HDRS and HARS were used to identify depression and anxiety. In conclusion, we confirmed in our survey high prevalence of pain, affecting approximately more than half of patients during the course of MS. Having in mind that pain in persons with MS is associated with disability and depression, it could potentially cause additional suffering and interfere significantly with daily activities. Until now, unfortunately the evidence for treating MS-related pain is very limited. Therefore, randomized controlled trials should be conducted to examine the efficacy and safety of various pharmacological treatments as well as nonpharmacologic therapies (psychotherapy, physical and occupational therapy). References 1 Moisset X, Ouchchane L, Guy N, et al. Migraine headaches and pain with neuropathic characteristics: Comorbid conditions in patients with multiple sclerosis. Pain 2013;154: Solaro C, Brichetto G, Amato MP, et al. The prevalence of pain in multiple sclerosis: A multicenter cross-sectional study. Neurology 2004;63: Foley PL, Vesterinen HM, Laird BI, et al. Prevalence and natural history of pain in adults with multiple sclerosis: Systematic review and meta-analysis. Pain 2013;154: O Connor AB, Schwid SR, Herrmann DN, Markman JD, Dworkin RH. Pain associated with multiple sclerosis: Systematic review and proposed classification. Pain 2008:137: Grond S, Radbruch L, Meuser T, et al. Assessment and treatment of neuropathic cancer pain following WHO guidelines. Pain 1999;79: Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald Criteria. Ann Neurol 2005;58: Kurtzke JF. Rating neurological impairment in multiple sclerosis: an expandeddisability status scale (EDSS). Neurology 1983;33: McCormack HM, Horne DJ, Sheather S. Clinical applications of visual analogue scales: a critical review. Psychol Med 1988;18: Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23: Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959;32: Hadjimichael O, Kerns RD, Rizzo MA, Cutter G, Vollmer T. Persistent pain and uncomfortable sensations in persons with, multiple sclerosis. Pain 2007; 127: Osterberg A, Boivie J, Thuomas KA. Central pain in multiple sclerosis prevalence and clinical characteristics. Eur J Pain 2005;9: Seixas D, Sa MJ, Galhardo V, Guimaraes J, Lima D. Pain in Portuguese patients with multiple sclerosis. Front Neurol 2011;2: Hooge JP, Redekop WK. Trigeminal neuralgia in multiple sclerosis. Neurology 1995;45: Rushton JG, Olafson RA. Trigeminal neuralgia associated with multiple sclerosis. Arch Neurol 1965;13: Ehde DM, Gibbons LE, Chwastiak L, et al. Chronic pain in a large community sample of persons with multiple sclerosis. Mult Scler 2003;9: Svendsen KB, Jensen TS, Overvad K, et al. Pain in patients with multiple sclerosis: a population-based study. Arch Neurol 2003;60: Moulin DE, Foley KM, Ebers GC. Pain syndromes in multiple sclerosis. Neurology 1988;38: Chwastiak L, Ehde DM, Gibbons LE, Sullivan M, Bowen JD, Kraft GH. Depressive symptoms and severity of illness in multiple sclerosis: Epidemiologic study of a large community sample. Am J Psychiatry 2002;159: Feinstein A. Multiple sclerosis and depression. Mult Scler 2011;17: Alschuler KN, Ehde DM, Jensen MP. The cooccurrence of pain and depression in adults with multiple sclerosis. Rehabil Psychol 2013;58:

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