In this cross-sectional study, the prevalence of NEP among all pwMS was about 40%. Higher EDSS and longer disease duration caused increased incidence of NEP. The results of our study did not indicate a possible relationship between NEP and MS therapies since all of the patients described NEP before the onset of treatments. However, patients with comorbid-psychiatric disorders had significantly higher rates of NEP.
Several studies showed that pain is a disabling symptom in MS, and the prevalence of pain in pwMS was reported to be between 29–86% [20, 21]. The wide range of the estimated prevalence of pain may be related to study methodologies, evaluation of different types of pain, application of various questionnaires, and structured interview methods . Likewise, the prevalence of NP varies across studies due to the involvement of pwMS at different stages, non-specific and non-standard assessment tools, and patients suffering from other types of pain . LANSS and DN4 scales are reliable tools to assess NP and have over 80% sensitivity and specificity. Therefore, we used both LANSS and DN4 scales to distinguish NP from nociceptive pain. Several studies based on DN4 have examined a potential association between NEP and MS; some of them found an association between these two conditions. According to those studies, the overall incidence of NEP in pwMS ranges from 6–28% [4, 11, 20]. From our data, it appears that the frequency of NEP in pwMS (40%) is compatible with other studies [9, 15].
NP can be provoked by several risk factors in MS, but the exact mechanism is still unknown. Several studies reported that age, female gender, longer disease duration, progressive course of the disease, and higher EDSS score seemed to increase the risk of NP. In a cross-sectional multicenter study, a multivariate analysis showed that age, EDSS, gender, and disease duration were significantly associated with NP. They also reported that EDSS is an independent risk factor to precipitate NP compared to nociceptive pain .
In 2012, Truini et al. investigated the neurophysiological findings and pain mechanisms in pwMS. Patients with relapsing-remitting course had less frequent NP according to patients with progressive disease. Older age and longer disease duration were associated with pain; in addition, EDSS was the only significant factor related to NP . These results were not consistent with data from other studies [15, 25]. For instance, in a French study conducted by a postal survey, 51% of the participants reported NP; however, sex, age, and disease duration were not associated with NP . In accordance with the previous study, Labuz-Roszak et al. found no significant relationship between disease duration and NP .
During the natural course of MS, multiple demyelinating lesions may accumulate in the central nervous system affecting the somatosensory pathways. The migration of T-cells and the activated microglia induce tissue damage in spinothalamic pathways over time ; therefore, longer disease duration and higher disability due to increased lesion load may accompany NEP [4, 16]. From our data, it also appears that patients with NEP had a longer disease duration and a higher EDSS score. Although those patients had low disability status, we observed that patients with NEP had almost 2 times higher EDSS levels than those without NEP.
Disease-modifying treatments (DMTs) have several side effects. The majority of side effects of DMTs are not associated with pain; although, interferons may induce flu-like symptoms, joint pain, myalgia, and headache. In contrast, Doolen et al. reported that fingolimod might reduce NP in a mouse model by reversing central sensitization in the dorsal column of the spinal cord . Also, glatiramer acetate was found effective in preventing long-term allodynia and hyperalgesia by reducing the expression of the chemotactic fractalkine chemokine in the dorsal horn . In this study, we had the exceptional opportunity of observing NP whether it was induced by the use of all MS therapies in a relatively large group. As consistent with data from previous studies, we also have not seen a relationship between NP and DMTs [26, 27, 30].
Population-based prevalence studies demonstrate that about 14–54% of pwMS suffer from psychiatric disorders such as depression and anxiety, and this rate is 2 or 3-times higher than the normal population. The reason for this kind of wide range is due to differences in definitions, study designs, and diagnostic criteria, like in pain frequency [31, 32]. Disability, pain, and perception of chronic disease can trigger the emergence of depression and anxiety as well as structural or immunological factors in MS [31, 32, 33]. In our study, depression was detected in 6.6% of the patients and anxiety in 10% of the patients. All those pwMS with psychiatric disorders reported the presence of NEP. However, more data are needed to claim that psychiatric disorders cause NEP or pain reveals as a result of depression and anxiety.
QOL is the general well-being of individuals. In addition to depression and anxiety, many symptoms, including pain, disability status, sleep quality, and fatigue, can reduce the QOL in pwMS . In a recent study, Zhang et al. reported that depression, pain, fatigue, and anxiety are the major comorbidities affecting the QOL in pwMS. Besides, pain was strongly associated with "The Assessment of Quality of Life with Eight Dimensions" (AQoL-8D) physical domain and had the second-largest impact on the overall AQoL-8D . In the present study, we applied SF-36 to evaluate the QOL in pwMS. All domains of SF-36, except mental health in male patients, were significantly reduced compared to the normal population. In addition, we observed that QOL was more prominently affected in patients with NEP and psychiatric disorders. A longitudinal study revealed that treating both pain and depression is more effective than targeting either depression or pain . For this reason, treatment of NEP and psychiatric comorbidities together is essential to improve the QOL.
This cross-sectional study has several limitations. First, we do not have a control group consisting of healthy participants. Second, all participants were RRMS patients, and the study did not include MS patients with progressive course. Third, the range of EDSS was too narrow, and we did not evaluate the patients with high disability. Fourth, we did not evaluate the pain intensity.