Pain at Rest as a Predictive Factor of Chronic Pain Related to Central Sensitization in Patients With Hip Osteoarthritis

(CS) has been identied as a factor that induces chronic pain in patients with osteoarthritis (OA). Although there are some reports of CS in knee OA, on CS in hip OA are We to evaluate related to CS in with hip OA


Results
The mean CSI score was 19.54 ± 11.25 points. Twenty-one percent of the patients with a score of ≥ 30 were diagnosed as having chronic pain related to CS. The CSI score correlated signi cantly only with the VAS pain score at rest (r = 0.348, P < 0.001). Fifteen patients were diagnosed with CS syndromes (CSSs) in the assessment of CSI Part B. The mean CSI score was signi cantly higher in patients diagnosed with CSSs (30.00 ± 12.50) than in patients without a CSS (17.70 ± 10.00; P < 0.001).

Conclusion
Twenty-one percent of the patients scheduled to undergo THA for hip OA were diagnosed with chronic pain related to CS, which might in uence the clinical results after THA. As the VAS pain score at rest was signi cantly correlated with the CSI score, pain at rest might be a predictive factor of chronic pain related to CS in patients with hip OA. Background Osteoarthritis (OA) is a heterogeneous disease, characterised by progressive cartilage loss, subchondral bone remodelling, osteophyte formation, and synovial in ammation, with resultant joint pain and increasing functional disability. Patients with persistent pain due to OA complain of multiple symptoms that cannot be explained solely by structural changes. It has been reported that there is a poor correlation between structural and in ammatory changes in OA and pain levels. [1] Although the determinants of pain in OA are poorly understood, they are believed to involve multiple interactive pathways that are best explained by a biopsychosocial framework, which includes biological, psychological, and social factors. [2,3] We have occasionally encountered cases of patients with OA who complain of severe pain at rest.
Previous research suggests that OA-related pain at rest and on activity are weakly correlated. [4,5] However, the mechanism of the discrepancy between pain at rest and pain on activity remains unclear.
In 2011, the International Association for the Study of Pain de ned central sensitization (CS) as increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input. CS results from persistent, intense nociceptor stimulation that triggers changes in the central pain transmitting neurons, leading to alterations in pain presentation and perception, and centrally mediated symptoms, such as fatigue and mood disorders. [6] Over the last several decades, many authors have reported CS as one of the mechanisms underlying various chronic pain disorders, including headache, whiplash pain, musculoskeletal pain, low back pain, visceral pain, vulvodynia, prostatitis, etc. [7] CS has also been reported as a chronic pain factor in patients with OA. [8,9] Patients with chronic pain with a CS component have been reported to be resistant to conservative treatment, including traditional pain medication and physiotherapy. [10][11][12] Moreover, preoperative central modulation of pain is associated with poor outcomes after total knee arthroplasty. [13] Thus, surgeons should be attentive to patients with suspected CS involvement before surgery, as such patients might be at risk for unfavourable outcomes.
However, evidence regarding the identi cation of CS is scarce, especially in patients with hip OA. Therefore, we aimed to evaluate chronic pain related to CS in patients with hip OA before total hip arthroplasty (THA). Furthermore, we aimed to clarify the predictive factors of chronic pain related to CS in patients with hip OA by evaluating the characteristics of patients with and without CS involvement. It might be unknown factors which induce poor outcome after THA.

Methods
Ethical approval was obtained from our Institutional Review Board, and the study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The requirement for informed consent was waived because of the retrospective study design.

Patients
A total of 100 consecutive patients diagnosed with hip OA who were scheduled to undergo THA between November 2018 and September 2019 were retrospectively included in this study. Patients who were not diagnosed with hip OA and/or previously underwent a hip surgery on the same laterality were excluded.
For all patients, data of age, sex, and clinical assessments (the duration of hip pain (in months), severity of pain, and clinical scores) were collected at a preoperative outpatient clinic one month before surgery.
The severity of OA-related pain at rest and on activity was assessed using a numeric visual analogue scale (VAS). The severity was also evaluated clinically by the Harris Hip Score (HHS).

Assessment of CS involvement
Researchers have proposed various possible mechanisms to clarify the existence of a CS component using technological developments such as (functional) magnetic resonance imaging, quantitative sensory testing, and the measurement of cytokine and neurotransmitter levels. [8,9,[14][15][16] In addition, the CS Inventory (CSI) was recently developed as a comprehensive screening tool with high reliability and reproducibility to identify the existence of a CS component. [17,18] The CSI is a simpler and more costeffective detection method than other previously developed methods. The CSI comprises 2 parts: A and B. Part A is composed of 25 self-reported items that are scored from 0 to 100 points. Part A is designed to evaluate symptoms associated with CS. Part B screens for previous diagnoses of one or more speci c disorders, including seven separate CS syndromes (CSSs) (e.g., bromyalgia, chronic fatigue syndrome, temporomandibular joint disorder, irritable bowel syndrome, migraine or tension headaches, multiple chemical sensitivities, and restless leg syndrome). CS involvement is strongly suggested in these seven disorders, and a comprehensive disease concept, known as CSS, has been proposed. [19,20] Thus, the CSI was used as measure of CS involvement in the present study.
We provided an explanation of the Japanese version of the CSI (both parts A and B) to the patients, and the patients completed the CSI by themselves. Tanaka et al. reported that the Japanese version of the CSI is a useful and psychometrically sound tool, comparable to the English version, for assessing CSSs in Japanese patients with musculoskeletal disorders. [21] The CSI Part A score was divided into ve categories with increasing severity: subclinical (0-29), mild (30-39), moderate (40-49), severe (50-59), and extreme (60-100). As Neblett et al. reported that a CSI score over 30 might be indicative of the presence of CS, [22] we determined the number of patients with a CSI score of 30 points or above, as well as those with a score of 40 points or above. The CSI Part B was also completed to evaluate the prevalence of CSSs in the patients. Furthermore, the prevalence of patients with one or more CSSs was investigated.

Statistical analyses
Results are expressed as the mean and the standard deviation of the mean unless otherwise indicated. A sample size calculation was performed based on the study's main objective, which was to evaluate the correlation between CSI scores and signi cant variables. The minimum power level was set at 0.95. It was determined that we needed to include 97 patients to satisfy the expected effect size. Therefore, our sample size of 100 patients was deemed adequate. The relationships between the CSI score and age, duration of hip pain, VAS pain at rest, VAS pain on activity, and HHS were evaluated using the Spearman's correlation coe cient. In addition, CSI scores in patients with and without CSSs were compared using the Mann-Whitney U test. All statistical analyses were performed using Statistical Package for the Social Sciences software (version 25.0, IBM, NY, USA). P values < 0.05 were considered to indicate statistical signi cance.

Results
Patient demographics and clinical assessments are summarised in Table 1. The mean age was 63.92 ± 11.60 years, and there were 15 men and 85 women. All patients had hip OA, categorised as advanced and terminal stage on preoperative plain radiography. The mean duration of hip pain was 50.45 ± 53.09 months. The mean VAS score was 3.15 ± 2.73 for pain at rest and 6.06 ± 2.48 for pain on activity. The mean VAS score was signi cantly higher for pain on activity than for pain at rest (P < 0.01).  Table 2. Seventy-nine patients were classi ed as subclinical (score: 0-29), 16 were classi ed as mild (score: 30-39), 3 were classi ed as moderate (score: 40-49), 2 were classi ed as severe (score: 50-59), and none were classi ed as extreme (score: 60-100). Twenty-one percent of the patients had a score of 30 or more points, and 5% of the patients had a score of 40 or more points. Prevalence rates of CSS diagnoses according to CSI Part B are shown in Table 3. Fifteen percent of the patients were diagnosed with one or more CSSs. The variables associated with the CSI score among all patients are shown in Table 4. The CSI score signi cantly correlated with the VAS score for pain at rest (r = 0.348, P < 0.001). However, other factors, including age, duration of hip pain, VAS score for pain on activity, and HHS, were not signi cantly associated with the CSI score. Additionally, the CSI score was signi cantly higher in patients with one or more CSSs (30.00 ± 12.50) than in patients without a CSS diagnosis (17.70 ± 10.00; P < 0.001) ( Table 5).   *P < 0.05, **P < 0.01, ***P < 0.001 that patients with CSI scores ≥ 40 before vertebral fusion surgery exhibit higher patient-reported disability scores after surgery. [24] THA is recognised as a feasible treatment for hip OA, with great advantages in terms of early rehabilitation and recovery in the activities of daily living. [25] However, about 10% of the patients who undergo THA complain of persistent pain and poor outcomes at long-term follow-up. [26,27] Although the patient satisfaction after THA correlates best with pain, [28] the causes of pain after THA might be multifactorial and remain unclear. To our best knowledge, no study has reported THA clinical outcomes in patients with CS-related pain. From our results, it should be noted that a certain number of patients with hip OA have CS-related pain, which might in uence postoperative outcomes.
Moreover, we clari ed that a signi cant relationship exists between pain at rest and CSI scores in patients with hip OA in this study. In patients with OA, pain on activity might be a common phenomenon, while pain at rest may sometimes occur with a variety of pain complaints (e.g., from a dull ache to a sharp, stabbing pain). [29] Since the presence and severity of joint pain correlate poorly with structural evidence of joint damage, [1] a variety of different mechanisms might contribute to the occurrence of pain in OA.
Results of functional brain imaging studies suggest that pain at rest (or spontaneous pain) is associated with distinct patterns of abnormal brain activity. [30,31] Creamer et al. reported that a relatively high pain at rest, but not on activity, was associated with decreased pain thresholds in patients with knee OA. [32] Lundblad et al. reported that high preoperative VAS pain at rest was associated with the presence of CS component and was also associated with less pain relief at 18 months after TKA. [4] Kadum et al.
reported less functional improvement in patients who underwent total shoulder arthroplasty among those with higher preoperative pain at rest. [33] Despite differences in the targeted joints, pain at rest is considered to be more representative of a CS component than pain on activity. Based on the present study results, pain at rest might also be a predictor of CS-related pain in patients with hip OA.
The CSI was developed as a comprehensive screening tool for identifying the presence a CS component, as well as the presence of CSSs, with a high test-retest reliability. [17,18] We used the CSI to indicate CS involvement because it is simpler, less expensive, and more non-invasive than previous methods. Twenty-one percent of the patients scheduled to undergo THA for hip OA had a CSI score of 30 or more points. Thus, a certain number of patients with hip OA have a CS component. Since CS might in uence clinical outcomes, the existence of CS should be evaluated and noted. As the VAS score for pain at rest was signi cantly associated with the CSI score, pain at rest might be a predictive factor of chronic pain related to CS in patients with hip OA. The authors received no speci c funding for this work.

Availability of data and materials
The datasets supporting the conclusions of this article are included within the article. The raw data can be requested from the corresponding author.
Authors' contributions YO, KF, GI contributed to the conception and design the study. YO and KF wrote the manuscript. YO, KF, TK, MT, KaU, and NT participated in the data collection, and did the statistical analysis. GI and KeU edited the manuscript. MT supervised the study. All authors read and approved the nal manuscript.
Ethical approval and consent to participate This study was approved by the Ethics Review Board of Kitasato University (reference number:B 20-096).
The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.Written consent to participate was not applicable for this retrospective study.

Consent for publication
Not applicable

Competing interests
The authors declare that they have no competing interests.