Pain Characteristics and Associations with Quality of Life in Patients with Multiple Sclerosis in Lithuania

Background and objectives: Even though pain in multiple sclerosis (MS) patients is common and possibly associated with reduced quality of life, its exact prevalence and characteristics remain vaguely understood. We aimed to estimate the true extent of pain and its associations with quality of life in Lithuanian MS patients and to compare this data with that of a control group. Materials and Methods: Data were collected prospectively at the Department of Neurology, Lithuanian University of Health Sciences Kaunas Clinics. A face-to-face structured interview and a questionnaire were used to collect demographic and clinical data of the MS (n = 120) and control (n = 120) groups. The Expanded Disability Status Scale (EDSS) was used to quantify disability in the MS group. Scores ≥4/10 in the Douleur Neuropathique 4 questionnaire were classified as neuropathic pain. Patients were evaluated using the anxiety and depression subsets of the Hospital Anxiety and Depression Scale (HADS-A and HADS-D), the physical and mental component subsets of the Short Form-12 questionnaire (PSC-12 and MSC-12). Results: The MS and control groups did not differ in pain prevalence (76.7% vs. 65.9%, p = 0.064) or intensity. Lhermitte sign, lower limb, and face pain were more common in the MS group, whereas subjects in the control group were more often affected by lower back, neck, and joint pain. Neuropathic pain and pain lasting longer than 2 years were more common among pain-affected MS patients than among controls. MS patients with pain had higher EDSS, HADS-D, and HADS-A and lower PSC-12 scores than those without pain; however, no difference was found regarding the duration of MS or age. Males with MS and pain had higher MSC-12 and HADS-D scores in comparison to the same subset of females. Conclusions: Pain affects approximately three out of four patients with MS in Lithuania and is negatively associated with the mental and physical aspects of quality of life.


Introduction
Pain is a common and significant symptom of multiple sclerosis (MS) that should not be dismissed, as it is rated as one of the highest priorities by individuals with MS, even surpassing functions such as speech or bowel and bladder control [1]. However, data on pain in MS are heterogeneous and prevalence values as low as 43% and as high as 86% have been reported [2,3]. Neuropathic pain is the type of pain most closely related to the pathology of MS and is found even in patients with early MS, with increasing frequency in later disease stages [4]; however, nociceptive pain also poses a marked problem as it is associated with musculoskeletal dysfunction that is a significant feature of MS. In addition, the presence of pain is likely associated with lower physical and mental quality of life as pain frequently accompanies depression and anxiety and vice versa [5]. Despite the prominent clinical importance of pain, its characteristics in MS remain only vaguely understood, and this lack of data 3. Results

Associations between the Presence of Pain and Demographic and Clinical Characteristics
A total of 240 subjects were included in the study, their demographic and clinical data are presented in Table 1. The majority of MS patients (n = 119) were diagnosed with relapsing-remitting MS. Males had slightly higher EDSS scores than females (3.5 (2.4-4.5) vs. 2.5 (1.5-3.5), p = 0.021), no other differences between the genders in the demographic and clinical data were observed. The overall prevalence of pain differed neither between the MS and control groups nor between females and males in the MS or control groups. No differences were found between MS patients with pain and those who did not any pain regarding the duration of MS (9.0 (5.0-13.0) vs. 9.5 (5.0-13.0), years, p = 0.854) or age (44.0 (35.0-53.8) vs. 43.5 (28.5-49.8), years, p = 0.311).

Comparison of Pain Characteristics in the Multiple Sclerosis and Control Groups
Neuropathic pain and pain of more than 2 years' duration were more common among MS patients who were experiencing pain compared to that among the control subjects affected by pain (p < 0.001), whereas no difference was found in the prevalence of constant pain and the intensity of pain. The percentage of participants who reported analgesic use did not differ between the groups. The comparison of pain characteristics between the MS and control groups is presented in Table 2.  Differences in pain location were also observed with Lhermitte sign, lower limb, and face pain being more common in the MS group, whereas subjects in the control group were more often affected by lower back, neck, and joint pain (p < 0.05) ( Figure 1).

Associations between Pain and Both Phycical and Mental Aspects of Quality of Life
In the MS group, EDSS moderately correlated with HADS-D scores (r = 0.573, p < 0.001) and only weakly with HADS-A scores (r = 0.238, p = 0.009). Higher anxiety and depression levels and lower SF-12 scores were more common among MS patients than among controls regardless of their experienced pain. However, when comparing subjects without pain between the groups, only PSC-12 values were found to be lower in the MS group (data not shown). Therefore, it may be assumed that higher anxiety and depression levels in the MS group are caused by multiple factors, an important one being pain. Data on SF-12 and HADS scores with regard to the presence of pain are summarized in Table 3.
In the MS group, higher values of HADS-D scores and lower values of MSC-12 were found among males than among females (5.0 (4.0-10.0) vs. 4.0 (1.8-7.0), p = 0.011 and 40.6 (29.9-51.8) vs. 47.3 (37.6-57.5), p = 0.008) and the same was observed when comparing males with pain and MS to the same subset of females. No other gender-associated differences were detected (data not shown).

Associations between Pain and both Phycical and Mental Aspects of Quality of Life
In the MS group, EDSS moderately correlated with HADS-D scores (r = 0.573, p < 0.001) and only weakly with HADS-A scores (r = 0.238, p = 0.009). Higher anxiety and depression levels and lower SF-12 scores were more common among MS patients than among controls regardless of their experienced pain. However, when comparing subjects without pain between the groups, only PSC-12 values were found to be lower in the MS group (data not shown). Therefore, it may be assumed that higher anxiety and depression levels in the MS group are caused by multiple factors, an important one being pain. Data on SF-12 and HADS scores with regard to the presence of pain are summarized in Table 3.

Discussion
Our study showed a 76.7% prevalence of pain among MS patients that is slightly higher than the prevalence of 62.8% that was reported in a systematic review and meta-analysis of pain in adults with MS [8]. We did not identify any difference in the duration of MS between patients with and without pain, and these results are consistent with the ones reported in certain studies [9][10][11] and contradictory with others [2]. A major source of these variabilities is the lack of consistency in inclusion criteria, such as differences in the proportion of males and females, EDSS scores, MS types as well as other clinical and demographic characteristics, which can lead to different results, e.g., those assessed in the outpatient setting are likely to report lower values of pain intensity and prevalence of pain than those managed in the inpatient setting.
A meta-analysis showed that nearly half of MS patients suffered from headache (42.5%) and that the most common pain syndromes were neuropathic extremity pain 26.6%, back pain 20.0%, and Lhermitte sign 16.6% [8]. Although quantitative results in studies of different patient populations and study designs cannot be directly compared, it is notable that some similarities in results have been obtained: a similar percentage of MS group patients in our study suffered from extremity pain (34.2% reported lower-extremity pain and 28.5% upper-extremity pain), back pain (21.7%), and Lhermitte sign (13.3%); however, our results did not confirm the high prevalence of headache as only 7.5% of MS patients reported having headaches. This number was much lower than the value we had expected. Given that the main focus of this study was on the overall prevalence and characteristics of pain without emphasis on headache, there is some likelihood that higher prevalence would have arisen if additional questions about headache had been included in the questionnaire.
A noteworthy observation to emerge from the data comparison was the detection of lower MSC-12 and HADS-D scores among males with MS and pain in comparison to those for females with MS and pain. A similar observation was reported in another study that showed better self-reported physical and mental health among females with MS [12]. A possible explanation of our results is that in our study males had higher EDSS scores, and we also found that EDSS scores moderately correlated with the HADS-D score and only weakly or insignificantly with other scores. Higher EDSS scores in males were not surprising, as male gender is known to be independently associated with faster disability accumulation in relapsing-remitting and secondary progressive MS, e.g., it has been calculated that it takes 8 years after the initial onset of symptoms for males to reach EDSS 3, while females reach this level of disability after 10 years [13].
We found that 52.5% of MS patients and 38.3% of controls (percentages of all subjects in each group) used pain medications and these numbers were much lower in comparison to the ones reported in a study that used information from the Swedish Prescribed Drugs Register to analyze the data of more than 3000 MS patients and 4000 controls [14]. The study reported that 79.5% of MS patients and 59.2% individuals in the non-MS cohort were prescribed pain medication [14]. These differences can be accounted for in part by contrasting pain management strategies in Europe that were shown in a large-scale study in 16 countries [15], for example, in Sweden only 30% of participants felt that at times their pain medicines were not adequate to control their pain in contrast to 74% of respondents in Denmark [15]. In addition, in 2015 the defined daily dose per 1000 inhabitants per day of non-opioid analgesics and antipyretics was 60% lower in Lithuania and 40% lower in Denmark in comparison with Sweden (71.0 and 107.4 vs. 179.1) [16]. There are several possible factors that could contribute to the differences in analgesic use: cultural influences, variations in the accessibility of non-pharmacological pain management programs; physicians' prescribing habits; drug availability, pricing, and reimbursement; etc.
Finally, the prevalence of pain in the control group (65.9%) was higher than we had expected. Due to a lack of data on this topic, the comparison of our results to the ones of other studies is complicated; however, a study in the USA that included more than 5000 White, non-Hispanic participants reported that the prevalence of pain in this population was 59.7% [17], which is only slightly lower than our reported result. It is noteworthy to emphasize that the prevalence of pain in individuals without MS would be assessed more accurately by random sampling in the wider population; therefore, the results of this study should be interpreted with caution.
Finally, a number of potential shortcomings need to be considered. The most important limitation lies in the fact that this study mainly relied on self-reported data obtained using questionnaires or self-assessment scales. In addition, this was a small-scale single-center study; therefore, the inclusion of participants was limited, and we were unable to gather data on pain and its characteristics in different MS types. This study was not specifically designed to accurately evaluate the prevalence and characteristics of headache; therefore, caution must be taken when interpreting the reported low prevalence of headache.

Conclusions
This was the first cross-sectional study to address the question of the prevalence and characteristics of pain in Lithuanian MS patients and to compare their data to controls. This work has revealed that there are no major differences in the prevalence or in the characteristics of pain in Lithuanian MS patients in comparison with the data reported by other authors. The present findings might suggest several courses of action in order to improve the well-being of MS patients. Firstly, physicians should not underestimate the prevalence of pain among those with MS as well as its effect on the mental and physical aspects of quality of life. In addition, given the low rate of pain medication use, it is possible that a significant percentage of MS patients do not receive adequate pain treatment. Pain in MS should be recognized as an important problem that requires the utmost diligence.

Conflicts of Interest:
The authors declare no conflict of interest.