| Objective:To investigate the predictors,quantile differences,developmental trajectories,and heterogeneous characteristics of chronic pain after total knee replacement surgery(TKA),and to determine the relationship between pain catastrophizing,PTSD symptoms,and gene polymorphism and changes in knee pain over time.(1)To investigate the incidence and predictors of chronic pain at 3,6,and 12months after TKA,and to estimate the longitudinal relationship between KOOS pain score and pain catastrophizing under different covariates and the interaction between the predictors.(2)To explore the curvilinear relationship between KOOS pain score and major predictive variables,and establish the threshold of target predictive variables.(3)To explore the potential causal relationship between knee pain and major predictors in TKA patients;(4)To explore the development trajectory of chronic pain after TKA,characterize the heterogeneity trajectory and explore the characteristic differences between subgroups.(5)To explore the association between candidate gene polymorphisms and the occurrence of chronic pain after TKA..Method:Prospective cohort study design was adopted to select patients undergoing elective TKA surgery.Demographic variables,clinical variables and psychological variables were collected before surgery by questionnaire survey,and blood was collected and investigate acute pain within 3 days after surgery.The pain catastrophizing,PHQ9 score,TSK score,PTSD symptoms,pain,pain scale and KOOS scale were investigated before and 3,6 and 12 months after operation.Logistic regression analysis was used to explore the predictors of chronic pain at different times,levels and types after TKA.A generalized linear mixed model covering individual random effects was used to explore the correlation and interaction between KOOS pain score and major predictors.A generalized additive mixed model was used to explore the curving relationship between KOOS pain score and major predictors.Quantile regression was used to explore the heterogeneous effects of different predictors on KOOS pain scores with different quantiles.The derivative of smoothing parameters is estimated by finite difference and the threshold is established.Longitudinal data at equal time intervals before,6 months after,and 12 months after surgery were selected to assess the potential causality between the main predictive variables and KOOS scores using a random-intercept cross-lag panel model(RI-CLPM).Based on the longitudinal data,the latent class mixed model was used to explore the development trajectory and potential subgroups of KOOS score,and polynomial logistic regression analysis was used to explore the preoperative factors that significantly predicted the latent category trajectory.Genomic DNA was extracted from peripheral blood of the subjects,and Genotyping was performed using mass spectrometry on the Mass ARRAY Analyzer 4 system to detect COMT gene(rs4818:C>G,rs4680:G>A)two polymorphic loci and KCNJ6(GIRK2)rs2070995:C>T;PRKCA rs887797:G>A;KCNS1 rs734784:T>C;P2RY12rs3732765:G>A performed genotyping to explore the association between genetic polymorphism and the occurrence of chronic pain after TKA.Result(1)336 subjects with TKA reported 54.5%,48.5%and 38.9%CPSP pain-at-rest at 3,6 and 12 months after surgery,and 13.4%,9.5%and 2.7%CPSP moderate and severe pain-at-rest,showing a gradually decreasing trend.The incidence of pain-on-movement was 80.4%,75%and 80.4%,respectively,while the incidence of moderate to severe pain-on-movement was 25.6%,25.8%and 22.9%,respectively.(2)With contralateral knee pain and analgesic behavior as covariables,multivariate logistic regression results showed that:(1)Widespread pain:Compared with 0 sites,TKA patients with 3 or more sites of widespread pain had 3.05 times and4.55 times of risk of developing pain-at-rest and moderate to severe pain-on-movement3 months after surgery,and 3.37 times and 2.93 times of risk of pain-at-rest and pain-on-movement 6 months after surgery,and 3.49 times,3.01 times and 2.89 times of risk of pain-at-rest,pain-on-movement,moderate and severe pain-on-movement 12 months after surgery,respectively.(2)APSP:The OR values of pain-at-rest and pain-on-movement were 1.36(95%CI:0.98-1.92,p=0.028)and 1.88(95%CI:0.98-1.92,p=0.028)and 1.88(95%CI:1.10--3.45,p=0.029),and the OR value of moderate to severe pain-at-rest 6 months after surgery was 1.50(95%CI:1.03--2.17,p=0.03).The OR values of moderate to severe pain-at-rest,pain-on-movement and moderate to severe pain-on-movement 3 months after surgery were 1.54(95%CI:1.18--2.02,p=0.002),1.44(95%CI:1.09--1.93,p=0.011),1.46(95%CI:1.46)for each 1 point increase in average pain-on-movement of APSP 3 months after surgery.1.19 1.82,p<0.001),OR values of pain-on-movement and moderate and severe pain-on-movement at 6 months after surgery were 1.26(95%CI:1.00--1.59,p=0.052)and1.13(95%CI:0.98--1.29,p=0.09),and the OR value of moderate to severe pain-on-movement 12 months after surgery was 1.48(95%CI:1.20-1.84,p<0.001);(3)Predictive variable-SCQ comorbidity score:For each 1-point increase in SCQ comorbidity score,the OR value of moderate to severe pain-on-movement 6 months after surgery was 1.22(95%CI:1.08--1.39,p=0.002),and the OR value of the incidence of pain-on-movement 12 months after surgery was 1.19(95%CI:1.02-1.40,p=0.031);(4)Preoperative WHYMPI general activity:For each 1 point increase in preoperative activity level,the OR values of moderate and severe pain-on-movement at 3 and 12 months after surgery were 0.63(95%CI:0.41–-0.98,p=0.041)and 0.26(95%CI:0.14--0.46,p=0.003),respectively.(5)Preoperative KOOS-ADL:For each1 point increase in preoperative KOOS-ADL score,the OR value of moderate to severe pain-at-rest 6 months after surgery was 1.10(95%CI:1.04–-1.16,p<0.001);(6)Preoperative PCS score:For each 1 point increase in PCS total score,the OR values of pain-at-rest and pain-on-movement 12 months after surgery were 1.02(95%CI:1.01-1.04,p=0.007)and 1.03(95%CI:1.00-1.05,p=0.041),respectively.(6)Others:the risk of pain-on-movement in patients with regular physical activity in adulthood was reduced to 0.43 times in 3 months after surgery;Compared with general anesthesia alone,patients with general anesthesia combined with femoral nerve block had a 0.28-fold reduction in the risk of moderate to severe pain-on-movement 6 months after surgery.Compared with patients without drainage tube indwelling,patients with drainage tube indwelling after surgery had a 0.31-fold reduction in the risk of moderate to severe movement pain 12 months after surgery;Patients who received opioid treatment within 72 hours after surgery had a 2.36-fold increased risk of moderate to severe pain-at-rest 3 months after surgery.(3)GLMM analysis showed that PCS score was positively correlated with KOOS pain score before and after adjusting for different covariates(β=0.32,95%CI:0.29-﹣0.35,p<0.001);There was a significant interaction between PCS score and follow-up time,and the relationship between PCS and KOOS pain score was strongest 12months after surgery(β=0.53,95%CI:0.41-﹣0.65,p<0.001),followed by 6 months after surgery(β=0.42,95%CI:0.34-﹣0.51,p<0.001),3 months after surgery(β=0.24,95%CI:0.16-﹣0.33,p<0.001),the preoperative relationship between the two was the lowest,but with the largest intercept.After controlling for confounding variables and PCS scores,depression scores of PHQ9 did not significantly predict KOOS scores,while PTSD symptoms(β=0.10,95%CI:0.05-0.12,p<0.001),TSK score(β=0.38,95%CI:0.35-0.41,p<0.001)still independently predict KOOS pain score;The interaction between PCS and TSK significantly predicted KOOS pain score(β=-0.13,95%CI:-0.16-﹣0.0.10).(4)GAMM analysis showed that nonlinear modeling provided more information and greater prediction(explanatory bias 65.6%vs 69.9%,respectively),and there was a significant interaction between PCS and TSK score(F=42.660,p<0.001).The curve relationship between PCS score and KOOS pain score showed typical saturation effect,the curve relationship between TSK score and KOOS pain score showed typical threshold effect,the curve relationship between follow-up time and KOOS pain score showed L-shaped curve,and APSP showed a linear relationship with KOOS pain score basically.At low PCS levels,TSK showed an enhanced interaction with the effect of PCS on KOOS pain score,while at high PCS levels,TSK showed a buffering interaction with the effect of PCS on KOOS pain score.The critical threshold of PCS score for predicting KOOS pain score was established:13 points,that is,when PCS score exceeded 13 points,KOOS pain score did not increase with the increase of PCS score.The prediction efficiency of PCS threshold to predict the trend of KOOS pain score over time is better than threshold grouping reported in literature(the largest adjusted R~2 and smallest AIC),and PCS score of different threshold grouping can significantly predict the trajectory of KOOS pain score after surgery(p<0.001);(5)Heterogeneous effects of KOOS pain score based on quantile regression showed that:PCS total score,TSK score,PHQ depression score and APSP maximum pain score could significantly predict KOOS score in the condition mean,very low(0.1),low(0.3),medium(0.5),high(0.7)and very high(0.9)KOOS score.WHYMPI total activity score was only significantly correlated with KOOS pain score at the very high(0.9)quantile,and presented a typical U-shaped curve.In the regression of 0.1,0.3,0.5,0.7,and 0.9 quantiles,the drop rate of KOOS pain over time increased with the increase of quantiles,indicating that individuals with higher preoperative pain levels would benefit more from pain relief during TKA surgery.The regression coefficients of contralateral knee pain decreased in the very low(0.1),low(0.3),medium(0.5),high(0.7),and very high(0.9)KOOS pain scores,while the regression coefficients of generalized knee pain increased in the corresponding quantile.Compared with the behavior of taking painkillers on time,"mostly disobedient"has a positive effect on KOOS pain score in the quantile of 0.3 and above,and is a risky behavior.(6)RI-CLPM results showed that at the interpersonal level,PCS score was significantly correlated with KOOS pain score(r RIs=0.891,p=0.001),that is,those who reported higher PCS score,showed higher KOOS pain scores than the average population;There was no statistical difference in the correlation between the two at the individual level.At the in-person level,higher preoperative PTSD symptoms prospectively predicted higher KOOS pain scores in TKA patients 6 months after surgery(β=0.177,p=0.039),and higher KOOS pain scores at 6 months postoperatively predicted more severe PTSD symptoms at 12 months postoperatively(β=0.269,p=0.011),but there was no significant correlation at the interpersonal level(r RIs=0.477,p=0.140).At the in-person level,preoperative WHYMPI activity score could prospectively predict KOOS pain level 6 months after surgery(β=-0.189,p=0.023),and pain level 6 months after surgery could prospectively predict WHYMPI activity level 12 months after surgery(β=-0.301,p=<0.001),but there was no significant correlation at interpersonal level(r RIs=-0.407,p=0.056);(7)LCMM analysis showed that there was heterogeneity in the development trajectory of KOOS pain score in TKA patients from preoperative to postoperative 12months,which included four subgroups:class 1"moderate to severe pain group with minimum decline"(5.4%),Class 2"moderate to severe pain group with maximum decline"(11.9%),Class 3"moderate to severe pain group with moderate decline"(80.7%)and Class 4"mild pain unchanged group"(2.1%);Follow-up time significantly predicted KOOS pain score in class 2(β=-0.85,Se=0.08,p<0.001)and class 3(β=-0.49,Se=0.03,p<0.001),but fail to significantly predict KOOS pain score in class 1(β=-0.11,Se=0.13,p=0.389)and class 4(β=-0.04,Se=0.21,p=0.824).Polynomial logistic regression analysis showed that four preoperative variables could independently predict the development trajectory of latent categories,namely,SCQ comorbity score,APSP maximum pain,preoperative PCS score and contralateral knee pain.Compared with ideal group 2,class 1"moderate-high pain with minimal decline"and Class 3"moderate-high pain with moderate decline"were more likely to report a higher SCQ comorbidity score(Class 1:OR=1.56,p=0.004;Class 3:OR=1.30,p=0.010),higher APSP(Class 1:OR=2.51,p<0.001;Class 3:OR=1.34,p=0.016),and higher preoperative PCS score(Class 1:OR=1.06,p=0.007;Class 3:OR=1.03,p=0.024).(8)SNPs results showed that:(1)The TT carriers with the minimum allele of(1)KCNJ6 rs2070995 reported a higher course of movement pain 3 to 12 months after TKA,a higher KOOS pain score 12 months after TKA,but a lower preoperative KOOS pain score;Furthermore,the interaction between rs2070995 mutation and preoperative PCS score,preoperative depression PHQ9 score,and preoperative analgesic behavior significantly predicted preoperative KOOS pain score.(2)rs734784 mutation was significantly associated with moderate to severe pain-on-movement 12 months after TKA(codominant model:OR=2.22,95%CI:1.22-4.05,p=0.006,Bonferroni corrected p=0.030;Hyperdominant model:OR=2.19,95%CI:1.21-3.98,p=0.009,Bonferroni adjusted p=0.045),was also significantly associated with pain course 3-12 months after TKA,heterozygous CT type carrying the smallest allele was a risk factor.(3)COMT rs4818 mutation was significantly associated with moderate to severe pain-at-rest 3months after TKA(dominant model:OR=0.39,95%CI:0.17-0.85,p=0.017;Additive model:OR=0.45,95%CI:0.24-0.78,p=0.029),was a protective factor;However,rs4818 mutation significantly predicted moderate to severe pain-at-rest 12 months after TKA(codominant model:OR=17.05,95%CI:1.04-279.36,p=0.047;Dominant model:OR=13.95,95%CI 1.0-136.91,p=0.021;Hyperdominant model:OR=8.93,95%CI1.00-79.53,p=0.032),which was converted into a risk factor,but no statistical difference was observed between the two after Bonferroni correction.(4)rs4680mutation significantly predicted the risk of moderate to severe pain-on-movement 3months after TKA(codominant model:OR=3.14,95%CI:1.07-9.36,p=0.008,Bonferroni corrected p=0.004;Recessive model:OR=3.99,95%CI:1.41-11.52,p=0.009,Bonferroni adjusted p=0.045),and the risk of moderate to severe pain-on-movement 6 months after surgery(codominant model:OR=5.82,95%CI:1.94-18.33,p=0.002,p=0.010 after Bonferroni correction;Recessive model:OR=6.19,95%CI:2.13-18.80,p=0.001,Bonferroni adjusted p=0.005)and the risk of moderate to severe pain-on-movement 12 months after surgery(codominant model:OR=6.24,95%CI:2.15-19.98,p=0.001,p=0.005 after Bonferroni correction;Recessive model:OR=5.78,95%CI:2.06-17.95,p=0.001,Bonferroni corrected p=0.005;Additive model:OR=1.82,95%CI:1.17-2.85,p=0.008);Linear regression results showed that AA genotype reported more severe pain duration at 3-12 months after surgery and more severe KOOS pain score at 12 months after surgery,but no significant correlation with preoperative KOOS pain score.Conclusion(1)The incidence of chronic pain after TKA was relatively high.The incidence of pain-at-rest and moderate to severe pain-at-rest decreased gradually at 3,6 and 12months after TKA,while the incidence of pain-on-movement and moderate and severe pain-on-movement decreased slightly at first and then rose.(2)The presence of widespread pain before surgery can significantly predict pain-at-rest and pain-on-movement 3 to 12 months after surgery;Mean pain-at-rest of APSP could predict pain-at-rest and pain-on-movement 3 months after surgery,but only pain-at-rest 6 months after surgery,but not pain-on-movement.Average pain-on-movement of APSP could predict pain-at-rest and pain-on-movement 3 months after surgery,but only pain-on-movement 6 months and 12 months after surgery,but not pain-at-rest.SCQ comorbidity score predicted pain-on-movement at 6 and 12 months,but not pain-at-rest,and did not significantly predict chronic pain at 3 months.Preoperative activity level could only significantly predict moderate to severe pain-on-movement 3 and 12months after surgery,but not rest pain,and did not significantly predict chronic pain 6months after surgery.Preoperative KOOS-ADL significantly predicted the risk of moderate to severe pain-at-rest 6 months after surgery.Preoperative PCS score could only predict chronic pain 12 months after surgery,but not chronic pain 3 and 6 months after surgery.Regular physical exercise in adults was a protective factor for movement pain 3 months after surgery,combined femoral nerve block anesthesia was a protective factor for moderate to severe movement pain 6 months after surgery,and indwelling incision drainage tube was a protective factor for moderate to severe movement pain 12months after surgery.(3)With the extension of time,PCS score and chronic pain after TKA are always positively correlated,and the intensity of the relationship increases with time,which means that the longer the pain duration after TKA,the greater the influence of PCS on chronic pain after TKA.PTSD symptoms and TSK score could independently predict knee pain score,but depression score could not.PCS and TSK score showed enhanced interaction on knee pain in low level of PCS,and buffered interaction on knee pain in high level of PCS.(4)Pain catastrophizing,kinesophobia,depressed emotion and knee pain score of TKA patients showed curvilinear relationship,different threshold level of PCS score can significantly predict the TKA patients with preoperative and postoperative 12months of knee pain trajectory of over time,the higher the level of PCS,the worse the trajectory of TKA patients;(5)There is heterogeneity in the influence of different predictive factors on the distribution of knee pain conditions in TKA patients,which should be fully influenced by targeted intervention strategies to minimize the occurrence of chronic pain after TKA;(6)At the interpersonal level,PCS is a dynamic process that changes over time,and at the personal level,PCS is a relatively stable and persistent trait that does not change over time.At the in-person level,PTSD symptoms are likely to be the cause of chronic pain at the next time point,and chronic pain at the next time point is likely to be the cause of PTSD symptoms at the next time point,as is daily activity level,which alternates with chronic pain over time,and the two are cause-and-effect each other.Therefore,intervention strategies based on PTSD symptoms and activity are likely to be reliable targets for preventing the occurrence and development of chronic pain after TKA.In addition to timely and effective psychological intervention,a multidimensional and interdisciplinary service system and long-term follow-up intervention mechanism for TKA patients should be established to screen individuals with catastrophic cognitive tendency,which is of great significance to prevent the occurrence and development of chronic pain after TKA.(7)The inclusion of SCQ comorbidities score,APSP mean pain score,preoperative catastrophic cognitive PCS score,and lateral knee pain significantly improved the prediction of different trajectory of knee pain in TKA patients.Ideal Class 2 of individual reported lower levels of comorbidity score,lower the acute phase of the pain and the disaster of lower cognitive,medical personnel should be aimed at these factors to explore how to improve the management of comorbidity,how to more effectively to carry out the management of preventive analgesia,as well as how to preoperative disaster cognitive assessment and intervention,The possibility of these measures in changing the postoperative pain trajectory of TKA was evaluated.(8)rs2070995 polymorphism of KCNJ6 gene was significantly correlated with chronic pain after TKA and knee pain before TKA,but the relationship was opposite.The interaction of rs2070995 mutation with psychological variables and medication behavior is beneficial for future research.Heterozygous CT type at rs734784 was significantly associated with pain 12 months after TKA,but the role of homozygous CC type with the smallest allele needs to be studied in a larger cohort of TKA patients.The protective effect of rs4818 mutation of COMT gene on moderate to severe pain-at-rest 3 months after TKA and the risk effect on moderate to severe pain-at-rest 12 months after TKA need to be verified by sample size with greater statistical power.Rs4680mutation of COMT gene can significantly predict the risk of moderate to severe pain-on-movement 3-12 months after TKA,but has no significant association with preoperative knee pain score.This difference reveals the different etiological mechanism of preoperative TKA pain and postoperative chronic pain.Future studies should include the assessment of neuropathic pain to further explore the pathogenesis of CPSP. |
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