Non-opioid analgesic combinations following total hip arthroplasty (RECIPE): a randomised, placebo-controlled, blinded, multicentre trial.

BACKGROUND: Multimodal postoperative analgesia following total hip arthroplasty is recommended, but the optimal combination of drugs remains uncertain. The aim of the RECIPE trial was to investigate the relative benefit and harm of the different combinations of paracetamol, ibuprofen, and the analgesic adjuvant dexamethasone for treatment of postoperative pain following total hip arthroplasty. METHODS: The RECIPE trial was a randomised, blinded, placebo-controlled trial conducted at nine Danish hospitals. Adults scheduled for total hip arthroplasty were randomly assigned (1:1:1:1) using a computer-generated list with stratification by site to receive combinations of oral paracetamol 1000 mg every 6 h, oral ibuprofen 400 mg every 6 h, or a single-dose of intravenous dexamethasone 24 mg in the following groups: paracetamol plus ibuprofen, ibuprofen plus dexamethasone, paracetamol plus dexamethasone, and paracetamol plus ibuprofen plus dexamethasone. The primary outcome was 24 h intravenous morphine consumption, analysed in a modified intention-to-treat population, defined as all randomly assigned participants who underwent total hip arthroplasty. The predefined minimal important difference was 8 mg. Safety outcomes included serious and non-serious adverse events within 90 days and 24 h. The trial was registered with ClinicalTrials.gov, NCT04123873. FINDINGS: Between March 5, 2020, and Nov 15, 2022, we randomly assigned 1060 participants, of whom 1043 (589 [56%] women and 454 [44%] men) were included in the modified intention-to-treat population. 261 were assigned to paracetamol plus ibuprofen, 262 to ibuprofen plus dexamethasone, 262 to paracetamol plus dexamethasone, and 258 to paracetamol plus ibuprofen plus dexamethasone. Median 24 h morphine consumption was 24 mg (IQR 12-38) in the paracetamol plus ibuprofen group, 20 mg (12-32) in the paracetamol plus dexamethasone group, 16 mg (10-30) in the ibuprofen plus dexamethasone group, and 15 mg (8-26) in the paracetamol plus ibuprofen plus dexamethasone group. The paracetamol plus ibuprofen plus dexamethasone group had a significantly reduced 24 h morphine consumption compared with paracetamol plus ibuprofen (Hodges-Lehmann median difference -6 mg [99% CI -10 to -3]; p<0·0001) and paracetamol plus dexamethasone (-4 mg [-8 to -1]; p=0·0013), however, none of the comparisons showed differences reaching the minimal important threshold of 8 mg. 91 (35%) of 258 participants in the paracetamol plus ibuprofen plus dexamethasone group had one or more adverse events, compared with 99 (38%) of 262 in the ibuprofen plus dexamethasone group, 103 (39%) of 262 in the paracetamol plus dexamethasone group, and 165 (63%) of 261 in the paracetamol plus ibuprofen group. INTERPRETATION: In adults undergoing total hip arthroplasty, a combination of paracetamol, ibuprofen, and dexamethasone had the lowest morphine consumption within 24 h following surgery and the most favourable adverse event profile, with a lower incidence of serious and non-serious adverse events (primarily driven by differences in nausea, vomiting, and dizziness) compared with paracetamol plus ibuprofen. FUNDING: The Novo Nordisk Foundation and Næstved-Slagelse-Ringsted Hospitals' Research Fund.

Glucocorticoids added to paracetamol and NSAIDs for post-operative pain: A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as the basic pain treatment regimen for most surgeries. Glucocorticoids have well-known anti-inflammatory and anti-emetic properties and may also demonstrate analgesic effects. We assessed benefit and harm of adding glucocorticoids to a combination of paracetamol and NSAIDs for post-operative pain management. METHODS: We searched Embase, Medline and CENTRAL for randomised clinical trials investigating the addition of glucocorticoids versus placebo/no intervention to paracetamol and an NSAID in adults undergoing any type of surgery. We assessed three primary outcomes: cumulative opioid consumption at 24 h postoperatively, serious adverse events and pain at rest at 24 h postoperatively. We performed meta-analysis and trial sequential analysis (TSA), assessed risk of bias using the Risk of Bias 2 tool and used the Grading of Recommendations Assessment, Development and Evaluation approach to evaluate the certainty of the evidence. RESULTS: We identified 12 relevant trials of which nine trials randomising 804 participants were included in quantitative analysis. When added to paracetamol and NSAIDs, we found no evidence of a difference of glucocorticoids versus placebo/no intervention in cumulative opioid consumption at 24 h postoperatively (mean difference [MD] -0.28, TSA-adjusted 95% confidence interval [CI] -1.90 to 1.33, p = .68, moderate certainty of evidence), serious adverse events (risk ratio (RR) 0.99, TSA-adjusted 95% CI 0.27-3.63, p = .93, very low certainty of evidence) or pain on the Numeric Rating Scale at 24 h postoperatively (MD -0.39, TSA-adjusted 95% CI -0.84 to 0.17, p = .10, moderate certainty of evidence). All outcomes were assessed to be at high risk of bias and TSA showed that we had insufficient information for most outcomes. CONCLUSION: Glucocorticoids added to a baseline therapy of paracetamol and an NSAID likely result in little to no difference in cumulative opioid consumption and pain at rest at 24 h postoperatively. In addition, the evidence is very uncertain about the effect on serious adverse events. For most outcomes we did not have sufficient information to draw firm conclusions and the certainty of the evidence varied from moderate to very low. EDITORIAL COMMENT: Multimodal approaches for post-operative analgesia are favoured, including paracetamol and nonsteroidal anti-inflammatory drugs. In this meta-analysis, pooled results from clinical trials are assessed to describe possible benefit of addition of glucocorticoid treatment for analgesia. The findings did not identify additional benefit, though the certainty of the evidence was not high.

Pain treatment after total hip arthroplasty: Detailed statistical analysis plan for the RECIPE randomised clinical trial.

BACKGROUND: The RECIPE trial systematically investigates the effects of different combinations of paracetamol, ibuprofen and dexamethasone for pain treatment after total hip arthroplasty. To preserve transparency, minimise risk of bias and to prevent data-driven analysis, we present this detailed statistical analysis plan. METHODS: The RECIPE trial is a randomised, blinded, parallel four-group multicenter clinical trial for patients undergoing planned primary total hip arthroplasty. Interventions are initiated preoperatively and continued for 24 h postoperatively. Primary outcome is total opioid consumption 0-24 h after end of surgery. Primary analysis will be performed in the modified intention to treat population of all patients undergoing total hip arthroplasty, and all analyses will be stratified for site. We will perform pairwise comparisons between each of the four groups. The primary outcome will be analysed using the van Elteren test and we will present Hodges-Lehmann median differences and confidence intervals. Binary outcomes will be analysed using logistic regression. To preserve a family-wise error rate of <0.05, we will use a Bonferroni-adjusted alfa of 0.05/6 = 0.0083 for all six pairwise comparisons between groups when analysing the primary outcome. We will systematically assess the underlying statistical assumptions for each analysis. Data will be analysed by two blinded independent statisticians, and we will write abstracts covering all possible combinations of conclusions, before breaking the blind. DISCUSSION: The RECIPE trial will provide important information on benefit and harm of combinations of the most frequently used non-opioid analgesics for pain after primary hip arthroplasty.