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.

Prolonged effects of dexamethasone following total knee arthroplasty: A pre-planned sub-study of the DEX-2-TKA trial.

OBJECTIVES: The DEX-2-TKA trial demonstrated that one and two doses of 24 mg intravenous dexamethasone reduced opioid consumption and pain after total knee arthroplasty (TKA). We aimed to investigate the prolonged effects of dexamethasone after the 48-h intervention period. DESIGN: This was a prospective, pre-planned questionnaire follow-up on postoperative days 3-7 of patients in the DEX-2-TKA trial that randomly received: DX1 (dexamethasone 24 mg + placebo), DX2 (dexamethasone 24 mg + dexamethasone 24 mg), and placebo (placebo + placebo) perioperatively and 24 h later. SETTING: A multicenter trial performed at five Danish hospitals. PARTICIPANTS: We analyzed 434 of 485 adult participants enrolled in the DEX-2-TKA trial. OUTCOME MEASURES: Primary outcome was difference between groups in average of all numerical rating scale (NRS) pain scores reported in the morning, at bedtime, and the daily average pain on postoperative days 3-7. Secondary outcomes were sleep quality and patient satisfaction. RESULTS: The median (interquartile range) pain intensity levels for postoperative days 3-7 were: DX2 3.2 (2.1-4.3); DX1 3.3 (2.3-4.1); and placebo 3.3 (2.5-4.7). Hodges-Lehmann median differences between groups were: 0 (95% confidence interval - 0.54 to 0.2), P = 0.38 between DX1 and placebo; 0.1 (-0.47 to 0.33), p = .87 between DX1 and DX2; and 0.1 (-0.6 to 0.13), p = .20 between DX2 and placebo. We found no relevant differences between groups on sleep quality on postoperative days 3-7 nor for patient satisfaction with the analgesic treatment. CONCLUSIONS: We found that neither one nor two doses of 24 mg intravenous dexamethasone demonstrated prolonged effects on overall pain or sleep quality on postoperative days 3-7 after total knee arthroplasty. We also found that dexamethasone had no effect on patient satisfaction. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT03506789 (main result trial).

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.