Objective To investigate the effects of one and two doses of intravenous dexamethasone in patients after total knee arthroplasty. Design Randomised, blinded, placebo controlled trial with follow-up at 90 days. Setting Five Danish hospitals, September 2018 to March 2020. Participants 485 adult participants undergoing total knee arthroplasty. Intervention A computer generated randomised sequence stratified for site was used to allocate participants to one of three groups: DX1 (dexamethasone (24 mg)+placebo); DX2 (dexamethasone (24 mg)+dexamethasone (24 mg)); or placebo (placebo+placebo). The intervention was given preoperatively and after 24 hours. Participants, investigators, and outcome assessors were blinded. All participants received paracetamol, ibuprofen, and local infiltration analgesia. Main outcome measures The primary outcome was total intravenous morphine consumption 0 to 48 hours postoperatively. Multiplicity adjusted threshold for statistical significance was P<0.017 and minimal important difference was 10 mg morphine. Secondary outcomes included postoperative pain. Results 485 participants were randomised: 161 to DX1, 162 to DX2, and 162 to placebo. Data from 472 participants (97.3%) were included in the primary outcome analysis. The median (interquartile range) morphine consumptions at 0-48 hours were: DX1 37.9 mg (20.7 to 56.7); DX2 35.0 mg (20.6 to 52.0); and placebo 43.0 mg (28.7 to 64.0). Hodges-Lehmann median differences between groups were: −2.7 mg (98.3% confidence interval −9.3 to 3.7), P=0.30 between DX1 and DX2; 7.8 mg (0.7 to 14.7), P=0.008 between DX1 and placebo; and 10.7 mg (4.0 to 17.3), P<0.001 between DX2 and placebo. Postoperative pain was reduced at 24 hours with one dose, and at 48 hours with two doses, of dexamethasone. Conclusion Two doses of dexamethasone reduced morphine consumption during 48 hours after total knee arthroplasty and reduced postoperative pain. Trial registration Clinicaltrials.gov NCT03506789 .

Background: Multimodal analgesia is considered the leading principle for postoperative pain treatment, but no gold standard after total knee arthroplasty (TKA) exists. Aim:To investigate the beneficial and harmful effects of one or two doses of 24 mg intravenous dexamethasone as part of a multimodal analgesic regimen (paracetamol, NSAID and perioperative local infiltration analgesia) after TKA. We hypothesise that addition of dexamethasone will reduce postoperative opioid consumption. Methods: 'DEXamethasone twice for pain treatment after TKA' (DEX-2-TKA) is a randomized, blinded, three-group multicentre clinical trial. Participants will be randomized to one of three groups: placebo, Accepted ArticleThis article is protected by copyright. All rights reserved single dose of dexamethasone, or two consecutive doses of dexamethasone. Participants, treatment providers, and investigators will be blinded to the allocated intervention. The primary outcome is total opioid consumption (units of morphine equivalents) 0-48 h postoperatively. Inclusion criteria: unilateral, primary TKA; age ≥18 years; American Society of Anesthesiologists (ASA)-Score 1-3; Body Mass Index ≥18 and ≤40; for women -not pregnant; and written informed consent. Exclusion criteria: allergy or contraindications against trial medication; daily use of high dose opioid and/or use of methadone/transdermal opioids; daily use of systemic glucocorticoids; dysregulated diabetes; and patients suffering from alcohol and/or drug abuse. Four-hundred-and-eighty-six eligible participants are needed to detect or discard a difference of 10 mg morphine equivalents 0-48 h postoperatively maintaining a family-wise error rate of 0.05 and a power of 90% for the three possible pairwise comparisons.

Background Optimization of post‐operative pain treatment is of upmost importance. Multimodal analgesia is the main post‐operative pain treatment principle, but the evidence on optimal analgesic combinations is unclear. With the “DEXamethasone twice for pain treatment after TKA” trial, we aim to investigate the role of one or two doses of glucocorticoid for post‐operative pain treatment after total knee arthroplasty. To ensure transparency and minimization of bias, we present this article with a detailed statistical analysis plan, to be published before the last participant is enrolled. Methods “DEXamethasone twice for pain treatment after TKA” (DEX‐2‐TKA) is a randomized, blinded, three‐group multicentre clinical trial. Participants will be randomized to one of three intervention groups: single dose of iv dexamethasone 24 mg, two consecutive doses of iv dexamethasone 24 mg or matching iv placebo. All three intervention groups will receive paracetamol, NSAID (ibuprofen) and local infiltration analgesia. Participants, treatment providers, outcome assessors, data managers, statisticians and conclusion drawers will be blinded to the allocated intervention. The primary outcome is total opioid consumption (iv morphine milligram equivalents) 0‐48 hours post‐operatively. Secondary outcomes are (1) visual analogue scale pain levels: (a) during active 45 degrees flexion of the knee at 24 and 48 hours post‐operatively, (b) at rest at 24 and 48 hours post‐operatively, and (c) during 0‐24 hours (highest score) and 24‐48 hours post‐operatively (highest score); and (2) the proportion of participants with one or more adverse events within 48 hours post‐operatively. Discussion The DEX‐2‐TKA trial will provide high quality data regarding benefits and harms of adding one or two high‐doses of dexamethasone to a multimodal analgesic regimen. Trial registration EudraCT: 2018‐001099‐39 (08/06‐18); ClinicalTrials.gov: NCT03506789 (24/04‐2019).

IntroductionMultimodal analgesia with paracetamol, non-steroidal anti-inflammatory drug and glucocorticoid is recommended for hip arthroplasty, but with uncertain effects of the different combinations. We aim to investigate benefit and harm of different combinations of paracetamol, ibuprofen and dexamethasone following total hip arthroplasty.Methods and analysisRECIPE is a randomised, placebo-controlled, parallel 4-group, blinded trial with 90-day and 1-year follow-up performed at nine Danish hospitals. Interventions are initiated preoperatively and continued for 24 hours postoperatively. Eligible participants undergoing total hip arthroplasty are randomised to:group A: oral paracetamol 1000 mg × 4+oral ibuprofen 400 mg × 4+intravenous placebo; group B: oral paracetamol 1000 mg × 4+intravenous dexamethasone 24 mg+oral placebo; group C: oral ibuprofen 400 mg × 4+intravenous dexamethasone 24 mg+oral placebo; group D: oral paracetamol 1000 mg × 4+oral ibuprofen 400 mg × 4+intravenous dexamethasone 24 mg.Primary outcome is cumulative opioid consumption at 0–24 hours. Secondary outcomes are pain at rest, during mobilisation and during a 5 m walk and adverse events. Follow-up includes serious adverse events and patient reported outcome measures at 90 days and 1 year. A total of 1060 participants are needed to demonstrate a difference of 8 mg in 24-hour morphine consumption assuming an SD of 24.5 mg, a risk of type I errors of 0.0083 and a risk of type 2 errors of 0.2. Primary analysis will be a modified intention-to-treat analysis.With this trial we aim to verify recommendations for pain treatment after total hip arthroplasty, and investigate the role of dexamethasone as an analgesic adjuvant to paracetamol and ibuprofen.Ethics and disseminationThis trial is approved by the Region Zealand Committee on Health Research Ethics (SJ-799). Plans for dissemination include publication in peer-reviewed journals and presentation at scientific meetings.Trial registration numberNCT04123873.

BACKGROUND Postoperative analgesic effects of systemic glucocorticoids given as an adjunct to treatment are largely undetermined in alloplastic procedures.OBJECTIVES To investigate the beneficial and harmful effects of peri-operative systemic glucocorticoid treatment for pain after total hip arthroplasty (THA) or total knee arthroplasty (TKA).DESIGN A systematic review of randomised clinical trials (RCTs) with meta-analyses, trial sequential analyses and GRADE. Primary outcome was 24 h intravenous (i.v.) morphine (or equivalent) consumption with a predefined minimal important difference (MID) of 5 mg. Secondary outcomes included pain at rest and during mobilisation (MID, VAS 10 mm), adverse and serious adverse events (SAEs).DATA SOURCES We searched EMBASE, Cochrane CEN-TRAL, PubMed and Google Scholar up to October 2021.ELIGIBILITY CRITERIA RCTs investigating peri-operative systemic glucocorticoid versus placebo or no intervention, for analgesic pain management of patients at least 18 years undergoing planned THA or TKA, irrespective of publication date and language.RESULTS We included 32 RCTs with 3521 patients. Nine trials were at a low risk of bias. Meta-analyses showed evidence of a reduction in 24 h cumulative morphine consumption with glucocorticoids by 5.0 mg (95% CI 2.2 to 7.7; P ¼ 0.0004). Pain at rest was reduced at 6 h by 7.8 mm (95% CI 5.5 to 10.2; P < 0.00001), and at 24 h by 6.3 mm (95% CI 3.8 to 8.8; P < 0.00001). Pain during mobilisation was reduced at 6 h by 9.8 mm (95% CI 6.9 to 12.8; P < 0.00001), and at 24 h by 9.0 mm (95% CI 5.5 to 12.4, P < 0.00001). Incidence of adverse events was generally lower in the glucocorticoid treatment group. SAEs were rarely reported. The GRADE rated quality of evidence was low to very low.CONCLUSION Peri-operative systemic glucocorticoid treatment reduced postoperative morphine consumption to an individually relevant level following hip and knee arthroplasty. Pain levels were reduced but were below the predefined MID. The quality of evidence was generally low.