Prevalence of neuropathic pain in patients with ankylosing spondylitis, relationship with disease parameters, depression, and sleep quality

Authors

Abstract

Aim This study aimed to investigate the neuropathic component of pain in ankylosing spondylitis (AS) patients and to assess its correlation with clinical parameters, depression, and sleep quality.
Materials and Methods The study included 80 AS patients along with 50 controls who were matched for age and sex. Disease activity was evaluated using the BASDAI and ASDAS; functional status with the BASFI; spinal mobility with the BASMI; quality of life with the ASQoL; sleep quality with the PSQI; depression with the BDI; and neuropathic pain (NP) with the PainDETECT questionnaire (PD-Q).
Results According to PD-Q, the proportion of NP was 28.75% in the AS group and 0% in the control group. Similarly, AS patients had higher points for BDI and PSQI (respectively, p = 0.003; p < 0.001). When AS patients were grouped according to PD-Q, the probable NP group had significantly higher points for VAS-pain (p < 0.001), ASQoL (p = 0.003), BASDAI (p < 0.001), ASDAS-ESR (p < 0.001), ASDAS-CRP (p < 0.001), BASFI (p < 0.001), BDI (p = 0.001), and PSQI (p < 0.001), relative to the uncertain NP and non-NP groups.
Discussion In our study, the presence of the neuropathic component of pain in patients with AS was identified compared to a control group. This situation was associated with high disease activity, limited functional status, poor quality of life, increased incidence of depression, and reduced sleep quality.

Keywords

Introduction

Clinical studies of ankylosing spondylitis (AS) patients in recent times showed that a correlation between pain and inflammation was not always present, and that there may be a neuropathic component of pain [1, 2]. The most striking feature of AS is inflammatory low back pain. Though available treatments control inflammation, patients may continue to have low back pain [2]. Along with nociceptive pain, patients may have symptoms like unexplained burning feeling, hyperalgesia, and allodynia, leading to the consideration that there may be a neuropathic component to pain [1, 3].
Neuropathic pain (NP) is pain due to somatosensorial system injury or disease, according to the IASP [4]. It may be due to the peripheral or central somatosensorial system [5]. The basic features of NP are continuous stimulation independent of stimulus, allodynia, and/or hyperalgesia [4]. Studies are showing the association of NP with rheumatic diseases such as primary Sjogren’s disease and rheumatoid arthritis [6, 7]. Additionally, some recently published studies report that AS pain may have both nociceptive and neuropathic components [8, 9]. A meta-analysis in recent times reported increased pain intensity, elevated disease activity, and reduced quality of life among AS patients with NP compared to those without [2].
Sleep disturbances are frequently observed among individuals with AS [10]. Studies have shown that sleep disorders are associated with nociceptive pain. High levels of disease activity negatively affect sleep quality. Fatigue, anxiety, and limited spinal movements are other factors that affect sleep quality [11]. However, the effect of NP regarding sleep quality among AS patients has not been sufficiently investigated in studies. This study was designed to evaluate the neuropathic component of pain in patients with AS compared to a control group and to explore its association with clinical parameters, depressive symptoms, and sleep quality.

Materials and Methods

Participants
This research was carried out as a single-center, cross-sectional analysis. Eighty sequential participants attending the Physical Medicine and Rehabilitation Department from May 2017 to January 2020, and with AS diagnosis based on the modified New York criteria, were included. Age- and gender-matched, fifty individuals were enrolled in the control group. In this study, we included patients whose disease was stable with treatment for at least the last 3 months. Patients whose disease is clinically unstable according to the history, clinical examination and test results, with other comorbid rheumatic diseases (rheumatoid arthritis, fibromyalgia etc.), with severe psychiatric disease, with disease of the nervous system (radiculopathy, polyneuropathy, stroke, spinal cord injury, etc.), with endocrine disease (thyroid dysfunction or diabetes mellitus), malignancy, previous NP diagnosis or receiving NP treatment were omitted from the study.
Clinical Assessment
Age, sex, disease duration, smoking, exercise status, educational level, occupation, current treatments, and laboratory values were recorded. Disease activity, spinal mobility, quality of life, functional status, sleep quality, depression, pain, and NP were assessed using specific scales.
NP was assessed with the pain DETECT questionnaire (PD- Q). Patients were categorised into three groups according to PD-Q score as those without NP ( score ≤ 12), with uncertain NP (score 13-18), and probable NP (score ≥19) [12]. Pain was assessed with VAS. Each patient marks the distance indicating their pain on a 10 cm scale. Here, the first three items on the PD-Q were used. Participants were requested to mark their pain in the current moment, the most severe pain in the last month, and the average pain in the last month on the scale.
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); disease-specific symptoms, including fatigue, pain in the spinal and peripheral joints, local sensitivity, and morning stiffness, were assessed with six questions. The score varies from 0-10. An increased score indicates increased disease activity. A BASDAI score of more than four shows active disease [13]. Ankylosing Spondylitis Disease Activity Score (ASDAS); This score combines patient reports and acute-phase reactants to assess both subjective and objective disease aspects [14].
Physical functions in AS were evaluated with the Bath Ankylosing Spondylitis Functional Index (BASFI). High BASFI scores indicate high functional disorder [15].
Quality of life was evaluated through the Ankylosing Spondylitis (ASQoL) Quality of Life Questionnaire developed for AS patients. High scores show there is a serious disruption to quality of life [16].
The 10-point Bath Ankylosing Spondylitis Metrology Index (BASMI) score was used to assess the axial skeletal mobility of AS patients. A high BASMI score implies that the patient has serious mobility restrictions.
Depression was evaluated with The Beck Depression Inventory (BDI). The BDI is a self-report, multiple-choice inventory commonly used to evaluate the existence and seriousness of depression [17].
The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality. Scores above 5 were interpreted as poor sleep quality [18].
Statistical Analysis
The sample size for this study was determined by a prior power analysis using G*Power 3.1.9.6 (UniversitätDüsseldorf, Düsseldorf) statistical software. The input parameters were Cohen’s suggestion medium effect size (0.3), a type I error rate (α) of 0.05, a power of 0.80, and a degree of freedom was 1 for the chi-square distribution. To test the significance of the chi- square test, a sample of at least 88 subjects in total is required in the patient and control groups.
Data normality was assessed using the Shapiro–Wilk test, and homogeneity of variances with the Levene test. Categorical variables were expressed as n (%), and continuous variables as mean ± standard deviation (SD), or median with interquartile range (IQR) and minimum–maximum values. The Student’s t-test was applied for normally distributed variables, and the Mann– Whitney U test for non-normal distributions when comparing AS and control groups. Participants were categorized into three subgroups based on PD-Q scores: no NP, uncertain NP, and probable NP. Comparisons among these subgroups were made using the Kruskal–Wallis test followed by the Dunn–Bonferroni post hoc test. Fisher’s Exact test was applied to analyze relationships between categorical variables. A p-value below 0.05 was accepted as statistically significant. All analyses were performed using SPSS version 28 (IBM Corp., Chicago, IL, USA).
Ethical Approval
This study was approved by the Ethics Committee of Ordu University (Date: 2021-11-05, No: 234).

Results

Comparison of Clinical Data in Patient and Control Groups
The study included 80 patients with AS and 50 healthy participants. Mean age in the AS group was 40.74 + 10.03 years (range 19-66 years; 51 men, 29 women), while mean age in the control group was 39.12 + 11.14 years (range 22-70 years; 33 men, 17 women). The AS group was found to have higher current pain (VAS-1), most severe pain in the last month (VAS-2), average pain in the last month (VAS-3), presence of NP according to PD-Q, median BDI score, and median PSQI score, and the differences were identified to be statistically significant. While the probable NP rate based on PD-Q was 28.75% for AS patients, no patient was identified to have NP in the control group, while uncertain NP was found in 2 people (4%).
According to the BDI, 20% (n = 16) of AS patients had moderate depression, and 8.8% (n = 7) had severe depression. When we analysed the control group, 8% (n = 4) had moderate depression, and severe depression was not observed. The difference was found to be statistically significant (p = 0.003, Table 1).
According to PSQI, 56.3% of AS patients (n = 45) and 18% of the control group (n = 9) did not have good sleep quality. The majority of the control group (82.0%) had good sleep quality. PSQI was approximately 6 times higher in patients with AS compared to the control group (OR: 5.895). The difference was statistically significant (p < 0.001, Table 1).
Comparison of Clinical Data of Patients According to PD-Q When AS patients were grouped according to PD-Q, the probable NP group had significantly higher points for VAS-1, VAS-2, VAS-3, ASQoL, BASDAI, ASDAS-ESR, ASDAS-CRP, BASFI, BDI, and PSQI scores compared to the uncertain and non-NP groups. BASMI was not different between the groups. Details can be seen in Table 2.
When compared according to BDI scores, the rate for moderate and severe depressive symptoms was higher at a statistically significant level in the probable NP group. Moderate depressive symptoms were present in 11.8% of the non-NP group (n = 4) and 30.4% of the probable NP group (n = 7), while severe depressive symptoms were present in 0% of the non-NP group (n = 0) and 21.7% of the probable NP group (n = 5) (p = 0.007).
When patients are assessed with PSQI, 62.5% of non-NP cases (n = 20) had good sleep quality, while 43.4% of uncertain NP cases (n = 10) had good sleep, and 17.4% of the probable NP group (n = 4) had good sleep quality. In terms of poor sleep quality, 37.5% of the non-NP group (n = 12), 56.5% of the uncertain NP group (n = 13), and 82.6% of the probable NP group (n = 19) were identified to have poor sleep. The difference was statistically significant (p = 0.04).
Post-hoc test results are shown with letters in Table 2. There was no significant difference between the uncertain and probable NP groups for BASDAI, ASDAS-CRP, ASDAS-ESR, BASFI, BDI, PSQI, VAS-1, VAS-2, and VAS-3 (p > 0.05). The non-NP group and probable and uncertain groups had significantly low BASDAI, ASDAS-CRP, and ASDAS-ESR values (p < 0.05). For ASQoL, the uncertain group, probable group, and non-NP group were not significantly different (p > 0.05). The ASQoL score in the probable NP group was significantly higher than the non-NP group (p < 0.05).
There were no significant correlations found between PD-Q points with ESR, CRP, and BASMI. There were positive, significant moderate correlations between PD-Q points with BASDAI, ASDAS-CRP, ASDAS-ESR, BASFI, ASQoL, BDI, and PSQI.
There was a strong correlation with VAS scores. Correlation coefficients and p-values can be seen in Table 3.
Comparison of Sleep Quality of the Groups According to PD-Q
Grouping according to PD-Q and PSQI scores also confirmed the relationship between NP and sleep quality. While 38.2% of AS patients without NP had poor sleep quality, this rate increased to 82.6% in those with NP. The risk of poor sleep quality was approximately 8 times higher (OR: 7.673) in those with NP compared to those without NP.

Discussion

In this study, the AS group’s NP frequency, as measured by the PD-Q, was shown to be statistically higher than that of the control group. The NP rate was 28.75% for patients and 0% for the controls. When AS patients were grouped among themselves according to PD-Q, the probable NP group had significantly higher VAS-pain, ASQoL, BASDAI, ASDAS-ESR, ASDAS-CRP, BASFI, BDI, and PSQI scores compared to the uncertain and non-NP groups.
Despite effective control of inflammation and improvement in acute-phase markers in AS, persistent pain remains a major problem. A mixed pain pattern is thought to develop with the addition of an NP component to the nociceptive pain present in AS [19]. Studies found that the NP component in AS has variable rates from 22.2% to 57.5% [1, 3]. In our study, the NP proportion among patients with AS was 28.75%. Differences in detection rates may be due to patient populations and differences in specificity and sensitivity of questionnaires used for NP diagnosis. Additionally, it may be due to differences in cut-off values in studies using the PD-Q.
In the literature, there are studies reporting negative impacts on disease activity, functional status, and quality of life with the presence of NP in AS patients. Atik et al. investigated correlations between PD-Q scores and clinical parameters in AS and identified that patients with NP component had higher BASDAI, ASDAS-ESR, and ASQoL scores [3]. Another study assessing LANSS and DN4 for NP in AS showed that AS patients with NP component had higher BASMI, BASDAI, and BASFI scores [8]. Similarly, in our study, the NP group had worse quality of life and functional status and higher VAS scores, and higher ASDAS-CRP, ASDAS-ESR, and BASDAI scores, showing disease activity. The presence of NP in AS, in addition to current pain, may cause pain to be felt more intensely and disrupt quality of life.
Anxiety and depression are frequently co-occurring psychological illnesses in AS patients. The prevalence of depression may reach 59.3% in patients with AS [20]. In our study, the incidence of depressive symptoms in AS patients was higher compared to the control group. Again, in our study, the probable NP group with AS had 30.4% rate for moderate depressive symptoms and 21.7% rate for severe depressive symptoms and these were statistically significantly high. According to this result, the frequency of depressive symptoms is clearly high, especially in AS patients with NP. Similarly, several studies in recent times showed that the frequency of depression was higher in AS patients with NP component [21, 22]. Studies showed that the correlation between pain and psychological factors is complicated and multidimensional. Psychological factors affect the perception of pain; similarly, the presence of pain affects psychological well-being and social participation. Effective management of depression in AS patients may alleviate NP severity; conversely, early detection and treatment of NP may lower the incidence of depression.
Another topic in AS is the more frequent observation of sleep disorders compared to the normal population. A meta-analysis by Salari et al. found 53 % of AS patients had sleep disorders [23]. In our study, similar to previous studies, sleep disorder was identified in AS patients. According to PSQI, 56.3% of AS patients and 18% of the control group did not have good sleep quality. Studies have reported that the most important cause of sleep disturbance in AS patients is nociceptive pain. In addition, it has been shown that factors such as spinal restriction, anxiety, disease duration, and fatigue affect sleep quality [8, 11, 24]. However, as far as we know, the effect of NP in AS on sleep quality has not been sufficiently investigated. Grouping according to PD-Q and PSQI scores confirmed the relationship between NP and sleep quality. In non-NP AS patients, 38.2% had poor sleep quality, while 82.6% of the probable NP group were identified to have poor sleep quality. AS patients with NP had an approximately 8-fold higher risk (OR: 7.673) of having poor sleep quality than those without NP. These findings lead to consideration that sleep disorder observed in AS patients may be due to NP component. We believe the appropriate treatment of NP in AS may ameliorate sleep quality. There is a need for more comprehensive studies of this topic.

Limitations

Our study has several limitations. Firstly, the NP component was assessed based on PD-Q. PD-Q is a tool commonly used to screen for the presence of NP in clinical practice that is easy to use and is self-report-based; however, there is a need for more objective evidence, like neuroimaging methods and somatosensorial tests, to reveal the pathophysiology of pain in AS. Secondly, we completed this study with 80 AS patients and 50 control cases. Multi-center studies with larger patient groups will be beneficial to obtain more definite results.

Conclusion

In this current study, we showed the presence of NP in patients with AS and the correlation of this situation with a variety of variables, like high disease activity, poor functional status, reduced quality of life, and increased depression incidence. Additionally, though it is known that sleep quality is poor among AS patients, it was revealed that the NP component may be a factor. Assessment of patients with AS in terms of NP and shaping treatment accordingly will be beneficial in terms of pain management.

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