Background To investigate the analgesic effect of perioperative use of duloxetine in patients received total knee arthroplasty (TKA). Method This prospective randomized, double-blind, placebo-controlled trial study was registered in the Chinese Clinical Trial Registry (ChiCTR2000033910). 100 patients were finally enrolled. The hospital pharmacy prepared small capsules containing either duloxetine or starch (placebo) which were all identical in appearance and weight (50:50). The 100 enrolled patients were given a capsule (containing either 60 mg duloxetine or 60 mg placebo) every night before sleep since preoperative day 2 till postoperative day 14 (17 days in all) by a nurse who were not involved in this trial. Other perioperative managements were the same in the two groups. The primary outcome was the VAS score, including rVAS (visual analogue scale at rest) and aVAS (visual analogue scale upon ambulation) throughout the perioperative period. The secondary outcomes included opioid consumption, range of motion, including both active range of motion (aROM) and passive range of motion (pROM) and adverse events. The patients were followed up everyday until 7 days after TKA, afterwards, they were followed up at the time of 3 weeks and 3 months after TKA. Result rVAS in duloxetine group were significantly less than placebo group throughout the postoperative period: 4.7 ± 2.3 vs 5.9 ± 2.6 (P = 0.016) at 24 h postoperative; 2.1 ± 1.6 vs 2.8 ± 1.7 (P = 0.037) at 7 days postoperative. In terms of aVAS, similarly, duloxetine group had less aVAS than placebo group throughout the postoperative period: 6.2 ± 2.1 vs 7.1 ± 2.2 (P = 0.039) at 24 h postoperative; 3.3 ± 1.7 vs 4.1 ± 2.0 (P = 0.034) at 7 days postoperative. Patients in duloxetine group consumed significantly less opioids per day than the placebo group: 24.2 ± 10.1 g vs 28.5 ± 8.3 g (P = 0.022) at 24 h postoperative; 2.7 ± 2.5 g vs 4.1 ± 2.6 g (P = 0.007) at 7 days postoperative. aROM in duloxetine group were significantly better than placebo group until postoperative day 6, the aROM became comparable between the two groups: 110.2 ± 9.9° in duloxetine group vs 107.5 ± 11.5° in control group (P = 0.211). In terms of pROM, duloxetine group had significantly better pROM until postoperative day 5, the pROM became comparable between the two groups: 103.8 ± 12.1° in duloxetine group vs 99.5 ± 10.8° in control group (P = 0.064). No significant difference was found between the two groups in the rates of dizziness, bleeding, sweating, fatigue and dryness of mouth. In the placebo group, more patients got nausea/vomiting and constipation (P < 0.05). However, in terms of drowsiness, duloxetine group was reported higher rate (P < 0.05). Conclusion Several other RCTs have already mentioned the analgesic effect of duloxetine, but not in the immediate postoperative period. In this study, we found duloxetine could reduce acute postoperative pain in the immediate postoperative period and decrease the opioids consumption as well as accelerating postoperative recovery, without increasing the risk of adverse medication effects in patients undergoing TKA. Duloxetine could act as a good supplement in multimodal pain management protocol for patients undergoing TKA. Trial registration statement This study was registered in the Chinese Clinical Trial Registry (ChiCTR2000033910). The date of registration was 06/16/2020.

Background Previous studies have demonstrated the efficacy of duloxetine in reducing postoperative pain and opioid consumption. However, the effect of duloxetine on total hip arthroplasty (THA) remains unclear. The objective of this study was to assess the efficacy of oral duloxetine in THA. Methods We enrolled 96 patients in this randomized controlled trial. These patients were randomized (1,1) to either the duloxetine group or the placebo group and received daily doses of 60 mg duloxetine or placebo, respectively, from 2 d pre-operation to 14 d after surgery. The primary outcome was pain severity upon movement measured by a visual analogue scale (VAS). The secondary outcomes included VAS scores for resting pain, morphine consumption, Harris Hip Score, patient satisfaction at discharge, length of postoperative hospital stay, and adverse events. Results Patients in the duloxetine group had significantly lower pain severity scores upon movement within 3 postoperative weeks (p < 0.05) while none of the differences met the minimum clinically important difference (MCID). Moreover, patients in the duloxetine group performed better in terms of resting pain (in 3 weeks after surgery), morphine requirements, and satisfaction level at discharge (all p < 0.05). There was no difference between groups in the prevalence of adverse events. Conclusions Although it did not result in a clinically meaning reduction in pain after total hip arthroplasty, perioperative administration of 60 mg of duloxetine daily significantly alleviated pain in the postoperative 3 weeks and morphine requirements during the postoperative 48 h. Therefore, duloxetine still shows promise in optimizing the multimodal pain-management protocols in total hip arthroplasty. Trial registration Chinese Clinical Trial Registry, ChiCTR2000033606, 06/06/2020.

Abstract. Shrinkage of empirical Bayes estimates (EBEs) of posterior individual parameters in mixedeffects models has been shown to obscure the apparent correlations among random effects and relationships between random effects and covariates. Empirical quantification equations have been widely used for population pharmacokinetic/pharmacodynamic models. The objectives of this manuscript were (1) to compare the empirical equations with theoretically derived equations, (2) to investigate and confirm the influencing factor on shrinkage, and (3) to evaluate the impact of shrinkage on estimation errors of EBEs using Monte Carlo simulations. A mathematical derivation was first provided for the shrinkage in nonlinear mixed effects model. Using a linear mixed model, the simulation results demonstrated that the shrinkage estimated from the empirical equations matched those based on the theoretically derived equations. Simulations with a two-compartment pharmacokinetic model verified that shrinkage has a reversed relationship with the relative ratio of interindividual variability to residual variability. Fewer numbers of observations per subject were associated with higher amount of shrinkage, consistent with findings from previous research. The influence of sampling times appeared to be larger when fewer PK samples were collected for each individual. As expected, sample size has very limited impact on shrinkage of the PK parameters of the two-compartment model. Assessment of estimation error suggested an average 1:1 relationship between shrinkage and median estimation error of EBEs.

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