Significance A moderate level of evidence was obtained for pain catastrophizing as an independent predictor of chronic post-surgical pain following total knee arthroplasty (TKA); Lack of uniformity in data capture, particularly in pain outcome measures, precludes meta-analysis and underscores the need for consensus regarding standardized reporting of chronic pain outcomes; Future directions for research include larger study samples, improved covariate adjustment (especially for analgesic use, depression, and anxiety), adoption of consensus guidelines on outcome measures for clinically relevant chronic pain, optimal thresholds for pain catastrophizing levels that predict adverse pain outcomes, and assessment of interventions aimed to reduce the negative effects of pain catastrophizing symptoms on chronic pain outcomes. Introduction With the aging population and mounting obesity epidemic, rates of TKA have increased dramatically in the last two decades such that TKA now constitutes one of the most common and costly medical procedures in the US and Canada.1–3 Although studies employing survivorship and surgeon-based measures have generally reported TKA success rates exceeding 80%,4 these measures do not account for post-surgical pain following TKA such that chronic pain remains a major health burden for many patients.5 Specifically, studies utilizing patient-based outcome measures have indicated that 6%–30% of patients continue to experience chronic pain in the months and years after TKA.6–10 This critical gap in recovery outcomes has prompted investigators to search for modifiable risk factors for chronic pain outcomes after TKA surgery. Converging evidence from the literature on non-surgical chronic pain suggests that pain disability does not result solely from the severity of the pain, but rather, is largely influenced by patients’ interpretation and adjustment to their pain.11–13 In particular, pain catastrophizing has emerged as an important factor in chronic pain onset, severity, and duration, and may represent an independent predictor of poor treatment outcomes including the development of chronic pain after surgery.14 Pain catastrophizing is a multidimensional construct comprising elements of rumination (ie, an anxious preoccupation with pain and the inability to inhibit pain-related thoughts and fears), magnification (ie, the tendency to amplify the significance of pain with respect to implications for one’s global health), and helplessness (ie, despair surrounding perceived inability to control one’s pain experience).15 Accordingly, high levels of pain catastrophizing have been shown to predict high levels of acute and persistent pain after various surgeries.16,17 Further, a recent systematic review of psychological risk factors for pain in total knee and hip arthroplasty included catastrophizing as a potential risk factor, although the search strategy employed was somewhat limited leading to the omission of key studies.18 Although prospective studies have emphasized the role of pain catastrophizing as a risk factor for poor pain outcomes following surgical procedures including TKA,19 the majority of research has employed the outcome of acute pain (ie, 0.05; Table 4). Neither of these studies reported odds ratios (ORs) with confidence intervals (CIs) for the TKA patients, masking potential trends and precluding future meta-analysis. Further, pre-operative anxiety emerged as an important predictor in both final models; however, the authors did not publish univariate or stepwise results from their logistic models. Thus, it remains unclear whether pain catastrophizing would have conferred a significant risk before depression and anxiety were added as covariates, which could again indicate collinearity of these constructs. Another small scale study (S2; n=55) assessed the impact of pain catastrophizing on a dichotomized definition of pain defining the presence of non-zero pain at 24 months follow-up as the primary outcome. The authors used two instruments to assess their outcome of non-zero pain: 1) the Short-Form MPQ–Pain Rating Index (PRI), which asks participants to rate adjectives that describe qualitative aspects of pain on a 4-point scale, and 2) the MPQ–VAS. Because the data were skewed, the authors employed Mann–Whitney U tests and receiver operating characteristic (ROC) curve analysis to assess the impact of catastrophizing on non-zero pain presence. The model using the adjective-based measure of non-zero pain (ie, MPQ–PRI), showed that both the total PCS score (PCS-T) and the rumination subscore (PCS-R) were significant predictors of the outcome (PCS-T, P=0.028, area under the curve =0.71; PCS-R, P=0.043, area under the curve =0.70). When the MPQ–VAS score was employed, however, the effect of catastrophizing lost significance (P’s from 0.56 to 0.71; Table 4). It is likely that the MPQ–PRI constitutes a more sensitive measure of variation among individuals with low-level pain because it prompts participants to consider different aspects of their pain experience, of importance in studies with extended follow-up intervals where floor effects can make relations difficult to detect. Nonetheless, caution should be exercised when interpreting these results given the small sample size, non-parametric analyses, failure to adjust for any covariates, and failure to adjust for multiple analyses, all of which increase the likelihood of false-positive findings. Finally, we identified a mid-sized (n=140) US case–control study (S5) that used TKA treatment failure (insufficient pain reduction) at 6 months follow-up as the case definition. The authors also used the PCS to measure preoperative pain catastrophizing, but chose to dichotomize this predictor variable according to high vs low catastrophizers. High catastrophizers were arbitrarily defined as those individuals in the highest tertile of obtained scores, corresponding to PCS scores ≥16, and all others were designated as low catastrophizers. It is noteworthy that the PCS manual provides cut-off scores for problematic pain catastrophizing; the selected threshold of ≥16 constitutes the cut-off score for the 41st percentile.34 Treatment failure was operationalized both in terms of 1) 1 year follow-up, the larger, more methodologically-rigorous study (S6) found an effect of catastrophizing on pain intensity, whereas the smaller unadjusted study (S2) found mixed results for an effect on non-zero pain, a divergence that likely reflects sensitivity differences in pain measures used. Thus, while length of follow-up may not interact with the strength of relation between pain catastrophizing and chronic pain outcomes, a floor effect may occur due to fewer chronic pain cases and/or general reductions in pain intensity with time. Discussion The objective of this systematic review was to provide a synthesis of the evidence to date on pain catastrophizing as a prospective risk factor for chronic pain (ie, persisting ≥3 months) after TKA. Overall, five out of the six identified studies were able to detect some effect of pain catastrophizing on chronic pain outcomes using at least one outcome measure. Although large-scale data were not available, two mid-sized multivariate cohort studies (S3 and S6) found a positive effect of pain catastrophizing on chronic pain intensity following TKA surgery independent of baseline demographics, pain levels, and psychological factors. Whereas, two mid-sized multivariate case–control analyses (S3 and S4) failed to replicate such an effect when clinically-meaningful pain thresholds were employed as case definitions and additional adjustment was made for anxiety and depression, another multivariable case–control study found that high pain catastrophizers had dramatically increased odds of TKA-treatment failure with respect to chronic pain outcomes (S5). A lagged analysis (S1) found that pain catastrophizing remained a stable predictor of future pain severity over 1 year follow-up, and a small unadjusted (S2) study found a measurable effect of catastrophizing on non-zero pain 2 years postoperatively. These data provide a moderate level of evidence that high pain catastrophizing is a risk factor for chronic pain following TKA. A major shortcoming in all identified studies was failure to report and adjust for analgesic use in multivariate models. It is possible that high pain catastrophizers had lower adherence to pain medications, perhaps due to heightened concerns regarding potential side-effects, which in turn may have led to poorer pain control at follow-up, thus confounding the investigated relations. Another important consideration that remains to be resolved is whether other psychological constructs (such as anxiety and depression), which are known to be related to pain catastrophizing, were measured and included as covariates in the model predicting chronic pain. For example, the global pain rating parameter estimate for pain catastrophizing in the lagged analysis (S1) lost significance after further inclusion of depression in the model, although nighttime pain remained significant after inclusion of depression. Further, the two non-significant case–control analyses that used clinically meaningful outcomes (S3 and S4) adjusted for anxiety and depression, although their potential impact on catastrophizing estimates was not reported. These studies suggest that depression and anxiety may be more relevant exposures, and to the extent that these are causally related to development of chronic pain, there are well-established treatments for both. In contrast, pain catastrophizing remained an independent predictor after controlling for anxiety (S3) and/or depression (S3, S4) in the two prospective multivariable cohort studies, which together constitute the highest level of evidence available to date. Taken together, we currently lack sufficient evidence to conclude which risk factor(s) among the many related psychological constructs (eg, pain catastrophizing, anxiety, and depression) contribute uniquely to chronic pain after TKA. In general, pain catastrophizing levels remained stable over follow-up, whereas pain levels gradually diminished, on average (Table 4). However, length of follow-up did not appear to modify the effect of catastrophizing on chronic pain outcomes measured, with no clear pattern of significance/non-significance observed as follow-up intervals increased. Rather, detection of a pain catastrophizing effect appeared to depend more on adequate power. Thus, the primary consideration in studies with lengthy follow-up periods (ie, >1 year) should be ensuring adequate numbers of cases or sufficient sensitivity in outcome measures to detect minor variability in low-grade pain. Nevertheless, without statistical analysis of large-scale data that models baseline catastrophizing on repeated pain measures over time, an interaction effect of follow-up time on the investigated relationship cannot be completely dismissed. We observed substantial heterogeneity in studies with respect to study designs, analyses employed, multivariate adjustments, measures used, and outcome reporting. Of particular importance, each study we identified employed a different outcome measure for pain. The failure to adopt standardized outcome measures of pain intensity as well as a relevant cut-off for clinically-meaningful pain precludes direct comparison of results and limits opportunities for meta-analysis. Authors did not typically report stepwise results of multivariate models or univariate parameter estimates to aid the reader in understanding the impact of collinearity. Furthermore, the identified studies did not report specific parameter estimates or confidence intervals for non-significant findings, limiting their interpretation and further precluding meta-analysis of small sample data. For instance, although three studies used logistic regression to assess the impact of pain catastrophizing on pain outcomes (S3, S4, S5), only the study with significant results (S5) presented ORs and CIs. Assessment of exposure was more consistent, with five of six studies employing the PCS. However, the one study that dichotomized patients as high vs low pain catastrophizers (a potentially valuable clinical distinction) failed to provide data on the validity of their threshold. To improve future data capture, the field would benefit from the adoption of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus guidelines for standardized reporting of clinically relevant pain outcomes in RCTs, which have direct relevance to both cohort and case–control studies as well.19,35–37 Multivariable adjustment should include analgesic use (type, dose), depression, and anxiety, in addition to traditional clinical risk factors. Further, investigation of the optimal PCS cut-off for ‘high pain catastrophizers’ in predicting adverse post-surgical pain outcomes (ROC analysis) would both set the stage for its inclusion in disease complexity measures in future investigations and would be of high clinical relevance as a practical screening tool. Finally, studies should report parameter and confidence estimates for non-significant findings so that future investigators may pool their data for powerful meta-analyses. Strengths and limitations of our systematic review deserve comment. Strengths of our review include a comprehensive and replicable research strategy with two independent raters and quality assessment of all articles by three independent raters, as well as a systematic approach to evidence synthesis on the predictive value of catastrophizing on chronic post-TKA pain. A limitation of our review is that the identification and selection of relevant articles may have been influenced by publication bias (ie, underreporting of non-significant findings). Further, due to the heterogeneity in data capture and reporting across the included studies, a quantitative meta-analysis was not possible. Although further well-controlled and large-scale data would be valuable, the current evidence provides moderate support that pain catastrophizing is an important risk factor for chronic pain following TKA surgery. Given that pain catastrophizing constitutes a modifiable response to threat among other populations of chronic pain patients38–40 and to the extent that it is a causal risk factor, interventions aimed at reducing pain catastrophizing symptoms41 may translate to improved pain outcomes of TKA. As rates of TKA continue to increase with the aging population and rising obesity epidemic,1,3 further clarification of the prognostic value of various pain catastrophizing levels holds promise to close the gap in TKA recovery outcomes.