IMPORTANCE Multimodal postoperative analgesia is widely used but lacks evidence of benefit. OBJECTIVE Investigate beneficial and harmful effects of 4 nonopioid analgesics regimens. DESIGN, SETTING, AND PARTICIPANTS Randomized, blinded, placebo-controlled, 4-group trial in 6Danishhospitalswith90-dayfollow-upthatincluded556patientsundergoingtotalhiparthroplasty (THA) from December 2015 to October 2017. Final date of follow-up was January 1, 2018. INTERVENTIONS Participants were randomized to receive paracetamol (acetaminophen) 1000 mg plus ibuprofen 400 mg (n = 136; PCM + IBU), paracetamol 1000 mg plus matched placebo (n = 142; PCM), ibuprofen 400 mg plus matched placebo (n = 141; IBU), or half-strength paracetamol 500 mg plus ibuprofen 200 mg (n = 140; HS-PCM + IBU) orally every 6 hours for 24 hours postoperatively, starting 1 hour before surgery. MAIN OUTCOMES AND MEASURES Two co-primary outcomes: 24-hour morphine consumption using patient-controlled analgesia in pairwise comparisons between the 4 groups (multiplicity-adjusted thresholds for statistical significance, P < .0042; minimal clinically important difference, 10 mg), and proportion of patients with 1 or more serious adverse events (SAEs) within 90 days (multiplicity-adjusted thresholds for statistical significance, P < .025). RESULTS Among 559 randomized participants (mean age, 67 years; 277 [50%] women), 556 (99.5%) completed the trial and were included in the analysis. Median 24-hour morphine consumption was 20 mg (99.6% CI, 0-148) in the PCM + IBU group, 36 mg (99.6% CI, 0-166) for PCM alone, 26 mg (99.6% CI, 2-139) for IBU alone, and 28 mg (99.6% CI, 2-145) for HS-PCM + IBU. The median difference in morphine consumption between the PCM + IBU group vs PCM alone was 16 mg (99.6% CI, 6.5 to 24; P < .001); for the PCM-alone group vs HS-PCM + IBU, 8 mg (99.6% CI, −1 to 14; P = .001); and for the PCM + IBU group vs IBU alone, 6 mg (99.6% CI, −2 to 16; P = .002). The difference in morphine consumption was not statistically significant for the PCM + IBU group vs HS-PCM + IBU (8 mg [99.6% CI, −2 to 16]; P = .005) or for the PCM-alone group vs IBU alone (10 mg [99.6% CI, −2 to 16]; P = .004) after adjustment for multiple comparisons and 2 co-primary outcomes. There was no significant difference between the IBU-alone group vs HS-PCM + IBU (2 mg [99.6% CI, −10 to 7]; P = .81). The proportion of patients with SAEs in groups receiving IBU was 15%, and in the PCM-alone group, was 11%. The relative risk of SAE was 1.44 (97.5% CI, 0.79 to 2.64; P = .18). CONCLUSIONS AND RELEVANCE Among patients undergoing THA, paracetamol plus ibuprofen significantly reduced morphine consumption compared with paracetamol alone in the first 24 hours after surgery; there was no statistically significant increase in SAEs in the pooled groups receiving ibuprofen alone vs with paracetamol alone. However, the combination did not result in a clinically important improvement over ibuprofen alone, suggesting that ibuprofen alone may be a reasonable option for early postoperative oral analgesia.

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.

Mitochondrial DNA (mtDNA) replication is thought to be an integral part of exercise-training-induced mitochondrial adaptations. Thus, mtDNA level is often used as an index of mitochondrial adaptations in training studies. We investigated the hypothesis that endurance exercise training-induced mitochondrial enzymatic changes are independent of genomic dosage by studying mtDNA content in skeletal muscle in response to six weeks of knee-extensor exercise training followed by four weeks of deconditioning in one leg, comparing results to the contralateral untrained leg, in 10 healthy, untrained male volunteers. Findings were compared to citrate synthase activity, mitochondrial complex activities, and content of mitochondrial membrane markers (porin and cardiolipin). One-legged knee-extensor exercise increased endurance performance by 120%, which was accompanied by increases in power output and peak oxygen uptake of 49% and 33%, respectively (p < 0.01). Citrate synthase and mitochondrial respiratory chain complex I–IV activities were increased by 51% and 46–61%, respectively, in the trained leg (p < 0.001). Despite a substantial training-induced increase in mitochondrial activity of TCA and ETC enzymes, there was no change in mtDNA and mitochondrial inner and outer membrane markers (i.e. cardiolipin and porin). Conversely, deconditioning reduced endurance capacity by 41%, muscle citrate synthase activity by 32%, and mitochondrial complex I–IV activities by 29–36% (p < 0.05), without any change in mtDNA and porin and cardiolipin content in the previously trained leg. The findings demonstrate that the adaptations in mitochondrial enzymatic activity after aerobic endurance exercise training and the opposite effects of deconditioning are independent of changes in the number of mitochondrial genomes, and likely relate to changes in the rate of transcription of mtDNA.

BackgroundTotal hip arthroplasty (THA) is a common procedure associated with moderate postoperative pain. No nerve block without loss of motor function has been documented for THA. We hypothesised that an ultrasound-guided lateral femoral cutaneous nerve (LFCN) block added to a multimodal postoperative pain regimen would reduce postoperative pain after THA.MethodsOne hundred patients who had a THA by the posterior approach were evaluated in this randomised, placebo-controlled, blinded, parallel-group trial comparing an ultrasound-guided LFCN-block with either 8 ml of ropivacaine, 7.5 mg/ml, (Group Ropivacaine) or 8 ml of saline (Group Placebo) given postoperatively. Surgery was performed under spinal anaesthesia. The primary outcome was pain (measured on a Visual Analogue Scale (VAS)) 4 h post-blockade during 30° flexion of the hip. Secondary outcomes were pain at rest, pain during movement, oxycodone consumption (0–24 h), time to mobilisation, ability to mobilise, and length of stay. Patients, assessors and all staff involved with patient care were blinded to the intervention.ResultsThere was no difference in primary outcome between Group Ropivacaine and Group Placebo (VAS 27 mm vs. 31 mm, p = 0.41; difference −5 mm (95 % CI: −15 mm - +5 mm). No differences in any of the secondary outcomes were observed. No adverse events, or harms, were observed during the trial.ConclusionPain scores, opioid use, time to mobilisation, and length of stay were low in both Group Ropivacaine and Group Placebo. We found no added analgesic effect of a LFCN-block when combined with paracetamol and ibuprofen after THA by the posterior approach.Trial registrationEudraCT: 2013-004501-12 (December 16th 2013)

LFCN block reduced movement-related pain in patients with moderate-to-severe pain after THA. The substantial non-responder rate limits recommendations of this block as part of a standard analgesic treatment regimen.

Background The available literature does not present a “gold standard” for post‐operative pain treatment after total hip arthroplasty (THA). The aim of this prospective observational study was to explore and document post‐operative pain treatment, including outcomes, in a large cohort of patients undergoing THA at five different Danish hospitals. Methods This prospective, multicentre, observational cohort study of 501 THA patients was performed at five different hospitals in the Capital Region and at the Region Zealand in Denmark, from April 2014 to April 2016. The study had two co‐primary outcomes: Pain during mobilisation at 6 hours post‐operatively (numeric rating scale [NRS] [0‐10]) and morphine consumption 0‐24 hours post‐operatively. Results A large variety of analgesic treatments were used at the included hospitals and none of the hospitals used the same non‐opioid basic analgesic regimen. For all patients at all hospitals, the NRS–pain level during mobilisation at 6 hours was 5 (3‐6), (median [interquartile range]) and the 24‐hour intravenous morphine (eqv) consumption was 25 mg (18‐35). Although some statistically significant differences between hospitals were found for morphine use, no non‐opioid analgesic regimen demonstrated consistent clinically relevant superior efficacy. In general, pain levels at rest were low to moderate and pain during mobilisation was moderate. Conclusions Analgesic treatment routines differed between hospitals. Pain levels, however, did not differ substantially and were in general low at rest and moderate during mobilisation. No non‐opioid analgesic treatment demonstrated consistent analgesic superiority.

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).