A prospective, observational study found that central sensitization and inflammation were important predictors for complex regional pain syndrome (CRPS) after total knee arthroplasty (TKA). These findings were published in the Journal of Pain.

Patients (N=110) scheduled to undergo TKA at Vanderbilt University Medical Center between 2017 and 2021 were recruited for this study. Prior to surgery, patients were evaluated for pain, psychosocial status, sleep disturbance, function, and inflammation. CRPS and inflammatory markers was evaluated at 6 weeks and 6 months. Patient preoperative characteristics were used to predict continuous CRPS Severity Score (CSS).

Patients were 64.5% women, aged median 68.0 (interquartile range [IQR], 9.0) years, 96.4% were White, and BMI was 30.9 (IQR, 7.6) kg/m2.

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At 6 weeks, 62.7% had a provisional diagnosis of CRPS, with 12.7% receiving a CRPS diagnosis at 6months.

At 6 weeks, patients with a provisional CRPS diagnosis had a significantly higher CSS score (median, 7.0 vs 4.0; P <.001), inflammation index (median, 4.0 vs 2.0; P <.001), and higher numerical rating scale (NRS) worst pain in the past 24 hours (median, 4.0 vs 2.0; P <.05).

More patients with a provisional diagnosis were associated with temperature asymmetry, skin color asymmetry, asymmetric edema, motor changes and allodynia or hyperalgesia (all P <.01).

At 6 months, patients with CRPS had a significantly higher CSS score (median, 6.0 vs 2.0; P <.001), inflammation index (median, 3.0 vs 2.0; P <.001), and higher NRS worst pain in the past 24 hours (median, 3.0 vs 2.0; P <.01).

CRPS was associated with temperature asymmetry, skin color asymmetry, asymmetric edema, motor changes, allodynia or hyperalgesia, and sweating asymmetry (all P <.05) at 6 months.

Among the 8 preoperative predictors of CRPS, 24 of the 36 comparisons were significantly correlated (all P <.05). Compared with outcomes, CSS at 6 weeks was correlated with preoperative Patient-Reported Outcomes Measurement Information System (PROMIS) sleep, McGill Pain Questionnaire-Short Form 2 (MPQ-2), Temporal Summation of Pain (TSP), State Trait Anxiety Inventory (STAI), Catastrophizing Scale (CATS), and Center for Epidemiological Studies-Depression Scale (CES-D) scores. CSS at 6 months correlated with preoperative MPQ-2 and TSP.

In the final model, CSS at 6 weeks was predicted by preoperative PROMIS sleep (β, 0.014; P =.001), tumor necrosis factor-alpha (TNF-α; β, 0.219; P =.009), TSP (β, 0.072; P =.009), MPQ-2 (β, 0.055; P =.010), CATS (β, 0.009; P =.011), STAI (β, 0.008; P =.032), and CES-D (β, 0.011; P =.043). At 6 months, predictors for CSS included preoperative MPQ-2 (β, 0.148; P <.001), PROMIS sleep (β, 0.043; P <.001), TNF-α (β, 0.375; P =.001), TSP (β, 0.113; P =.005), and MBM (β, 0.040; P =.005).

These findings may not be generalizable for CRPS following other surgeries.

This study found that at 6 months, patients with more widespread and intense preoperative pain, greater pain interference, and higher circulating TNF-α were more likely to be diagnosed with CRPS.


Bruehl S, Billings IV FT, Anderson S, et al. Preoperative predictors of complex regional pain syndrome outcomes in the 6 months following total knee arthroplasty. J Pain. 2022;S1526-5900(22)00303-0. doi:10.1016/j.jpain.2022.04.005