Neuropathic Pain Was Associated with Central Sensitivity Syndrome in Patients with Preoperative Lumbar Spinal Stenosis Using the painDETECT and Central Sensitization Inventory Questionnaires: A Cross-Sectional Study

Background Lumbar spinal stenosis (LSS) patients have been reported to have neuropathic pain and central sensitivity syndrome (CSS). These associations have been reported in other diseases but are unknown in preoperative LSS patients. We aimed to investigate the association between neuropathic pain and CSS in preoperative LSS patients using the painDETECT and the Central Sensitization Inventory (CSI) questionnaires. Methods This cross-sectional study was conducted from November 2021 to March 2022. The data were collected regarding demographics and pain, including neuropathic pain, numbness, LSS severity, physical function, quality of life, and CSS. Patients were divided into two groups, patients with acute and chronic pain, and further classified into three categories based on the clinical phenotype of patients in each group. Independent variables included age, gender, type of LSS (bilateral or unilateral symptoms), Numerical Rating Scale of leg pain, CSI, and the Zurich Claudication Questionnaire (ZCQ) for symptom severity and physical function. The dependent variable was painDETECT. Multiple regression analysis using the forced entry method examined the association between painDETECT and CSI. Results Of the 119 patients with preoperative LSS, 106 were included. The mean age of the participants was 69.9 years, and 45.3% were female. Neuropathic pain was present in 19.8%, and CSS was present in 10.4%. The CSI (β = 0.468, p < 0.001) and ZCQ for symptom severity (β = 0.304, p < 0.01) were significantly associated with the painDETECT, explaining 47.8% of the variance in the painDETECT score. Conclusions There is an association between neuropathic pain and CSS in patients with preoperative LSS using the painDETECT and CSI questionnaires.


Introduction
Lumbar spinal stenosis (LSS) is a degenerative disease impacting daily living and quality of life, with neuropathic pain being the primary complaint [1,2]. A previous study using the painDETECT, which can screen for neuropathic pain, reported that 17.6% of LSS patients were classifed as having neuropathic pain [3]. On the other hand, Miki et al. mentioned that 13% of patients with preoperative LSS and lumbar disc herniation had central sensitivity syndrome (CSS) [4]. Central sensitization (CS) is an essential element in understanding CSS. CS exhibits abnormal nociceptive systems with the enhancement of nociceptive pathways resulting from signifcant somatosensory nervous system plasticity [5]. CS and CSS are symptoms without a specifc organic cause [6]. Neuropathic pain and CSS involve abnormalities in the somatosensory system and may have similar clinical manifestations [7,8]. Furthermore, Akeda et al. stated that CSS might be associated with neuropathic pain symptoms caused by central or peripheral nervous system damage due to spinal disease [9]. For that reason, it is reported that CSS features have often been interchanged with neuropathic pain terms, leading to confusion [10]. In this way, the heterogeneity of the clinical symptoms and pathophysiology of LSS contribute to the difculty in understanding the source of pain [2]. Additionally, associations between neuropathic pain, CSS, and chronic pain have been reported, highlighting the importance of investigating these relationships for pain management and treatment in LSS patients [11][12][13][14]. Despite the association between neuropathic pain and CSS, no studies have investigated the potential association between the two in patients with preoperative LSS. Te investigation of these relationships will lead to an understanding of the mechanisms underlying pain. In addition, neuropathic pain and CSS have diferent treatment options, but there is potential to contribute to developing more efective treatments [15,16]. Tus, investigating these potential associations would be benefcial for pain management and treatment, and this study is the frst attempt to investigate preoperative LSS patients in this area.
In this study, we aimed to examine preoperative LSS patients for potential associations between neuropathic pain and CSS, hypothesizing that neuropathic pain and CSS would not be related. Rejecting this null hypothesis would imply a latent relationship between neuropathic pain and CSS, providing valuable insights for managing and treating pain in LSS patients.

Study Design and Setting.
Tis cross-sectional study was conducted between November 2021 and March 2022 at Shinagawa Shishokai Hospital. Te study was approved by the Shinagawa Shishokai Hospital Research Ethics Committee (reference no. 202101) and conducted in compliance with the Declaration of Helsinki. All participants provided written informed consent to participate following a comprehensive discussion about study procedures and objectives. Te study methods were compliant with the STROBE checklist [17].

Participants.
We included patients (1) who were hospitalized for surgery after being diagnosed with LSS, (2) who agreed to participate in the study, and (3) who were able to read the Japanese language well enough to complete the questionnaires independently. We excluded the following patients: (1) those with histories of musculoskeletal disorders and (2) those who did not complete the questionnaires.

Variables.
We collected data on age, gender, height, weight, body mass index (BMI), duration of LSS symptoms, and details of conservative treatments before surgery from medical records. Patients reported the duration of LSS symptoms in months or years. If the period was in years, it was converted to months. Chronic pain is pain that lasts or recurs for over three months [18]. Tis study classifed LSS symptoms lasting more than three months as chronic pain and those lasting less than three months as acute pain. Te type of LSS was classifed into bilateral or unilateral symptoms. LSS symptoms and radiological severity were assessed. In addition, we collected data on pain intensity, pain quality, CSS, LSS symptom severity, physical function, and quality of life by patient-reported outcome measures (PROMs). Before surgery, patients completed all PROMs. Te outcome measures are described in more detail in the following.
A taxonomy based on clinical phenotype was used to assess LSS symptoms. Based on the clinical phenotype of the patients, we classifed them into three categories: Type A, neurogenic claudication pain; Type B, neurogenic claudication sensory/balance; and Type C, radicular unilateral leg pain, based on the report of Comer et al. [19].
Te Schizas classifcation was used to assess the radiological severity of LSS [20]. Te participants were graded A (A1-A4), B, C, and D according to the classifcation by Schizas, which grades the cerebrospinal fuid ratio to nerve roots and spinal canal on a T2-weighted MRI scan of the spine. Te highest grade level was considered for the analysis of multiple spinal stenoses. Te planned surgical site determined the number and location of spinal stenosis.
Te Numerical Rating Scale (NRS) was used to rate the average low back, leg, and numbness intensity on the assessment day. A score of 0 indicated no pain, and 10 indicated the worst pain imaginable.
Te painDETECT was used to screen for neuropathic pain [21]. Tis questionnaire consists of nine items (seven pain-symptom items, one pain course, and one pain irradiation) completed on diferent scales. Te cutof values for pain categorization were nociceptive pain, 0-12; unclear pain (mixed nociceptive and neuropathic pain), 13-18; and neuropathic pain, 19-38. Te questionnaire reliability was previously confrmed (Cronbach's alpha � 0.83). Te pain-DETECT sensitivity is 84% and specifcity is 84%. Te Japanese version of the painDETECT is considered reliable and valid with a Cronbach's alpha of 0.80 and an intraclass correlation coefcient (ICC) of 0.943 [22].
Te Central Sensitization Inventory (CSI) was used to evaluate CSS. Te CSI is a self-report questionnaire that does not determine causality but can assess CS-related symptoms. Te CSI comprises 25 items with scores ranging from 0-4 [23]. Te higher the total score, the more signifcant the CS defcits; a total score of 40 is considered the cutof point. A cutof score of 40 out of 100 on the CSI has demonstrated excellent sensitivity (81%) for correctly identifying patients with CSS and acceptable specifcity (75%) for correctly identifying nonpatient comparison subjects [24]. In this study, a score of 39 or lower was considered a low CSI, and a score of 40 or higher was considered high [25]. Te Japanese version of the CSI is reliable and valid, with a Cronbach's alpha of 0.89 and an ICC of 0.85.
Te Zurich Claudication Questionnaire (ZCQ) was used to evaluate the LSS comprehensively [26]. Te 12-item ZCQ was developed to evaluate LSS comprehensively. Te symptom severity consists of 7 items with scores ranging from 1-5, and physical function consists of 5 items with scores ranging from 1-4. ZCQ scores range from 12-55, with higher scores indicating more dysfunction. Te Japanese version of the ZCQ is reliable and valid, with Cronbach's alphas of 0.78 (symptom severity) and 0.84 (physical function) and ICCs of 0.81 (symptom severity) and 0.89 (physical function) [27].
Te EQ-5D-5L was used to assess quality of life (QoL) [28]. Te Japanese version of the EQ-5D-5L consists of a 1 fve-item, fve-point categorical scale commonly used to measure the QoL. Te total score ranges from −0.025-1. A higher score on the EQ-5D-5L indicates good QoL. Te utility values are calculated from response integers using the formula reported by Ikeda et al.

Outcomes.
Te primary outcome was painDETECT and CSI. Multiple regression analysis was performed to evaluate these associations with painDETECT as the dependent variable and CSI and other items as independent variables. Details are described in the Statistical Variables section.

Bias.
Several strategies were implemented to minimize bias. All PROMs utilized standardized questionnaires with established reliability and validity in Japanese. Patients who required assistance comprehending the questionnaires or had incomplete data were excluded to guarantee a comprehensive data analysis. Moreover, the assessment date was designated as the day before surgery. Patients were informed that the evaluator and therapist might not be the same individual, ensuring that their questionnaire responses would not adversely afect their treatment.
2.6. Study Size. Te sample size was calculated using G * Power (version 3.9.6.1) [29,30]. G * Power uses the a priori power analysis method to calculate the necessary sample size based on the selected statistical analysis, desired power, and other input parameters. We entered the efect size, α error, power, and the number of predictors into the F tests to calculate the sample size. Te statistical test used was a linear multiple regression with a fxed model, focusing on R 2 deviation from zero. Te power analysis type involved calculating the required sample size based on α, power, and efect size." Specifcally, we set the efect size f2 to 0.15, αerr prob to 0.05, power to 0.8, and the number of predictors to 7, as Cohen [19] recommended for a medium efect size in psychological research. Te resulting sample size was 103 participants.

Quantitative Variables.
Participants' characteristics were summarized with descriptive statistics. Quantitative variables were presented for mean, standard deviation, minimum, maximum, median, interquartile range, and 95% confdence interval. Counts and percentages summarized categorical variables.

Statistical
Variables. For all variables, the Shapiro-Wilk test was used to assess the normality of the data distribution. For comparing continuous variables in the two acute and chronic pain groups, independent t-tests were used for variables meeting the normality assumption (p > 0.05). Otherwise, the Mann-Whitney U test was used. Categorical variables were examined with a chi-square test (expected frequency >5) or Fisher's exact probability test. Independent t-tests were used for the following items: height, painDE-TECT, ZCQ, ZCQ for symptom severity, and ZCQ for physical function. Independent Mann-Whitney U tests were used for the following items: age, weight, BMI, duration of LSS symptoms, number of spinal stenosis, NRS for LBP, leg pain, numbness, CSI, and EQ-5D-5L. Independent chisquare tests were used for the following items: gender. Independent Fisher's exact test was used for the following items: classifcation of LSS by the site of symptom appearance, grade of spinal stenosis according to Schizas, and conservative treatment. Two groups, acute and chronic pain, were classifed into three types, each using a clinical phenotype. Each factor's correlation was evaluated using Spearman's rank correlation coefcient (r). In addition, multiple regression analysis using the forced entry method was performed using painDETECT as the dependent variable and age, gender, and grade of classifcation of LSS by the site of symptom appearance, CSI, ZCQ for symptom severity, and ZCQ for physical function as independent variables to determine which factors afected the painDETECT score. Regarding multicollinearity, we confrmed that the analysis of variance (VIF) for all independent variables was <5. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) and GUI of R (the R Foundation for Statistical Computing, Vienna, Austria).

Participants' Characteristics.
We screened 119 participants with LSS; 13 (8%) were excluded due to previous surgery (n � 9), inability to understand (n � 1), difculty understanding Japanese (n � 1), and incomplete data (n � 2). Finally, 106 participants satisfed all criteria and agreed to participate. Characteristics of the participants and clinical features of the total sample are shown in Table 1. A comparison of the demographic and clinical characteristics of acute and chronic pain is shown in Table 2. Signifcant diferences were observed in gender, duration of LSS symptoms, classifcation of LSS by site of symptom appearance, number of spinal stenosis, and NRS for LBP. Table 3 shows the correlation matrix for all participants. Te painDETECT was positively associated with the NRS for low back pain, leg pain, and numbness (r � 0.341, p < 0.001, r � 0.428, p < 0.001, r � 0.429, p < 0.001), CSI (r � 0.550, p < 0.001), ZCQ for symptom severity (r � 0.523, p < 0.001), and ZCQ for physical function (r � 0.308, p < 0.001) and negatively associated with the EQ-5D-5L (r � −0.426, p < 0.001). Te CSI was positively associated with the NRS for low back pain, leg pain, and numbness (r � 0.444, p0.001, r � 0.327, p < 0.001, r � 0.293, p < 0.001), ZCQ for symptom severity (r � 0.307, p < 0.001), and ZCQ for physical function

Discussion
Tis was the frst study to investigate the potential association between neuropathic pain and CSS in preoperative patients with LSS using painDETECT and CSI. Te results showed a signifcant association between the painDETECT and CSI by multiple regression analysis. Furthermore, we also found an excellent convergent association between painDETECT and CSI, as 47.8% of the variance was explained. Tese fndings confrm the association between neuropathic pain and CSS in preoperative patients with LSS. Te painDETECT and CSI were nonsignifcant between the two groups for acute and chronic pain. No signifcant association was found between painDETECT and CSI in classifying LSS according to clinical phenotype. Similar to previous studies, leg symptoms in LSS included a neuropathic pain component in this study [2]. As leg symptoms in LSS result from the narrowing of the spinal canal, neuropathic pain is unlikely to infuence symptom duration. Terefore, we consider that the diference between the two groups due to acute and chronic pain was nonsignifcant. CSS is associated with CS, which is more common in patients with chronic pain [31]. Te mechanisms of CSS require further understanding. CSS has been observed even with nonpainful stimulation, and it has been reported that pain augmentation is unlikely to be a signifcant causal factor in CSS [6]. Since pain is unlikely to trigger CSS, we consider the diference between the two groups concerning acute and chronic pain nonsignifcant. Additionally, the nonsignifcant diference between the two groups may be attributed to the screening tools not containing questions related to symptom duration. We also speculate that the diference between the two groups is nonsignifcant because these screening tools do not have questions related to the duration of symptoms. Te classifcation of LSS by clinical phenotype is a recently developed classifcation method. For this reason, no investigation of each factor using this classifcation method has been conducted to date. In a previous study, patients with LSS were divided into two groups, one with predominant radicular pain and the other with predominant neurogenic intermittent claudication (NIC). Te group with predominant radicular pain had a higher LANSS score in identifying neuropathic pain [2]. However, the present study found an association between clinical phenotype and painDETECT. Although the creation mechanism of NIC development has not been elucidated, it is currently thought to be due to decreased blood fow to the nerve root and venous stasis [1,32]. Furthermore, leg pain in LSS is caused by nerve root compression, classifed as neuropathic pain. Terefore, we consider that the clinical phenotypes classifed into three types were not signifcantly diferent in painDETECT. In that study, patients with radicular pain that did not improve upon fexion were classifed into the radicular pain group. In this study, however, the classifcation is based on the clinical phenotype of the patients. In addition, painDETECT uses a fve-point Likert scale, while LANSS uses a two-point Likert scale. Diferences in the criteria for classifying patients with LSS and the screening tool used led to diferences in the results from previous studies. CSI also showed no signifcant association with clinical phenotype. Tanaka et al. reported that CSI is a clinical utility prediction tool for CSS regardless of the type of diagnosis [33]. Terefore, we speculate that although there is a certain number of CSS in the disease LSS, we did not fnd signifcant diferences by symptom because there is no organic cause.
Furthermore, in a previous study in which patients with LSS were classifed by painDETECT, 17.6% had neuropathic pain [3], and 17.9% of the study subjects had neuropathic pain. Furthermore, in a previous study of patients with preoperative LSS and lumbar disc herniation, 13.1% had high CSI [4], and 10.4% of the subjects had high CSI. Both neuropathic pain and CSI showed similar rates as in previous studies. Te reason for this is considered to be a similar patient background. Similar to other conditions, this study confrmed a potential link between painDETECT and CSI [11,12]. Te signifcant association between painDETECT and CSI in patients with preoperative LSS is a new fnding. Two studies examined the association between the pain-DETECT and CSI. Te frst study, involving participants recruited from the Spanish Fibromyalgia Association, consisted of women with fbromyalgia who had scores of 19.9 ± 7.1 and 70.7 ± 11.6 for painDETECT and CSI, respectively [12]. Another study was of outpatients on longterm follow-up for rheumatoid arthritis with scores of 7.48 ± 5.21 and 18.3 ± 11.8 for painDETECT and CSI, respectively [11]. Te previous study, as well as the present study, showed an association between painDETECT and CSI. However, there are diferences in painDETECT and CSI scores for each disease. Te mechanism of the disease may infuence the reason for this. LSS afects the cauda equina, epidural pressure, and nerve roots by reducing the spinal canal and foraminal space [34], and nerve root compression has been reported to cause neuropathic pain [35]. Terefore, neuropathic pain was considered to be observed in the subjects of this study. CSS has been defned as symptoms with no specifc organic cause but is associated with CS [36]. It is currently unknown whether pain augmentation afects CSS [6]. Te appearance of primary and secondary hyperalgesia characterizes neuropathic pain. An increased response to stimuli is primary hyperalgesia. Secondary hyperalgesia is thought to be caused by sensitization of the central nervous system [37]. It has also been reported that peripheral nerve damage can lead to CS [38]. Terefore, CSS was considered to be observed in the subjects of this study. In addition, two studies used the painDETECT to investigate signs of CS. One study included preoperative patients with 8 Pain Research and Management Table  3: A matrix of the correlations. hip osteoarthritis. Functional magnetic resonance imaging was used to evaluate the sharpness of point stimuli and changes in brain activity that occurred in response to stimulation [39]. Patients with high painDETECT scores (above the sample median) were likelier to show signs of CS.
Another study included patients with knee osteoarthritis and higher modifed painDETECT scores. Teir results revealed a lower pressure threshold for pain when assessing CS [29]. Terefore, painDETECT scores appear to be associated with signs of CS. Also reported was a possible association between neuropathic pain and CSS in patients with rheumatoid arthritis and patients undergoing elective spinal surgery [9,11,30]. Furthermore, it has been reported that medication restored or enhanced the descending pain suppression system in patients with chronic nerve root pain and diabetic polyneuropathy [40,41]. Descending pain inhibitory systems have been involved in CS [42,43], and CS is observed in neuropathic pain [44]. Tese reports may further emphasize the overlapping mechanisms and associations between neuropathic pain and CSS. Unfortunately, the mechanisms linking neuropathic pain and CSS are yet to be elucidated. However, an essential reason for the signifcant association between the painDETECT and the CSI might be the overlap between each other's questions. Te questions "Does your pain radiate to other regions of your body?" in painDETECT and "I feel pain all over my body" in CSI are considered overlapping. In addition, painDETECT provides seven questions on pain symptoms. CSI has provided a question on "My muscles feel stif and achy," "My legs feel uncomfortable and restless when I am trying to go to sleep at night," and "I have pain in my pelvic area." Patients may have responded to these question scales as identical. Terefore, caution is needed in interpreting the relevance of these questionnaires. Te exact mechanism by which compression of the lumbar spinal canal and neural foramen manifests as symptoms is not yet understood [1]. Terefore, the key to managing LSS, in which pain is the main symptom, is a comprehensive pain assessment.
One of the limitations of this study is that the subjects were only patients with preoperative LSS, which does not allow for application to primary care or postoperative patients. Because we only examined preoperative patients with LSS from a single institution, our results may need to be more generalizable to other patient groups or settings.
Furthermore, LSS has been reported to present with various symptoms, including NIC and LP, with diferent symptom mechanisms. However, the present study was not conducted on a symptom-by-symptom basis. Future surveys by symptom type would yield new results. Second, neuropathic pain and CSS were assessed using painDETECT and CSI. Diagnosing neuropathic pain requires detailed assessment, including neurologic examination [45]. CSS is also a symptom associated with CS, and Quantitative Sensory Testing (QST) is used to assess CS [46,47]. Terefore, neuropathic pain and CSS are inadequately assessed. However, the present study aimed to investigate potential associations of the screening assessment using a questionnaire. Terefore, the questionnaires were standardized. Tird, neuropathic pain and CSS have been associated with psychosocial factors [48], none of which were assessed in our study. Many CSI items have been reported to be common elements of anxiety and depression [33]. Furthermore, patients with higher CSI scores have reported improved depressive symptoms in chronic spinal pain disorders with a program that included education, counseling, and physical training [49]. Te association between neuropathic pain and CSS might have been better investigated if psychosocial factors were included. Finally, our data were cross-sectional and therefore captured one moment in time. Terefore, causal relationships cannot be confrmed.

Clinical Implication
First-line treatment for neuropathic pain is pharmacologic therapy. When inefectiveness is not expected, invasive approaches are considered [15]. A multidisciplinary approach that includes physical, cognitive, and pharmacotherapy is recommended as the frst-line treatment for CSS [16]. Te present study suggests an association between neuropathic pain and CSS in patients with preoperative LSS evaluated. Terefore, symptoms of LSS that have been judged as neuropathic pain may have aspects of a CSS. Interventions for CSS and neuropathic pain may improve symptoms of LSS.

Conclusion
Tis study investigated the potential association between neuropathic pain and CSS in patients with preoperative LSS using painDETECT and CSI. Tese results suggest neuropathic pain was associated with CSS in patients with LSS preoperatively assessed by painDETECT and CSI.

Data Availability
Te datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

Ethical Approval
Tis study was approved by the Shinagawa Shishokai Hospital Research Ethics Committee and conducted in compliance with the Declaration of Helsinki.

Consent
All participants provided written informed consent to participate following a comprehensive discussion about study procedures and objectives.

Disclosure
Reprints are not available from the authors.

Conflicts of Interest
Te authors declare that they have no conficts of interest.