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AbstractObjectiveTo investigate the effects of one and two doses of intravenous dexamethasone in patients after total knee arthroplasty.DesignRandomised, blinded, placebo controlled trial with follow-up at 90 days.SettingFive Danish hospitals, September 2018 to March 2020.Participants485 adult participants undergoing total knee arthroplasty.InterventionA 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 measuresThe 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.Results485 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.ConclusionTwo doses of dexamethasone reduced morphine consumption during 48 hours after total knee arthroplasty and reduced postoperative pain.Trial registrationClinicaltrials.gov NCT03506789.

Infant pain has immediate and long-term effects but is undertreated because of a paucity of evidence-based analgesics. Although morphine is often used to sedate ventilated infants, its analgesic efficacy is unclear. We aimed to establish whether oral morphine could provide effective and safe analgesia in non-ventilated premature infants for acute procedural pain. In this single-centre masked trial, 31 infants at the John Radcliffe Hospital, Oxford, UK, were randomly allocated using a web-based facility with a minimisation algorithm to either 100 μg/kg oral morphine sulphate or placebo 1 h before a clinically required heel lance and retinopathy of prematurity screening examination, on the same occasion. Eligible infants were born prematurely at less than 32 weeks' gestation or with a birthweight lower than 1501 g and had a gestational age of 34–42 weeks at the time of the study. The co-primary outcome measures were the Premature Infant Pain Profile–Revised (PIPP-R) score after retinopathy of prematurity screening and the magnitude of noxious-evoked brain activity after heel lancing. Secondary outcome measures assessed physiological stability and safety. This trial is registered with the European Clinical Trials Database (number 2014-003237-25). Between Oct 30, 2016, and Nov 17, 2017, 15 infants were randomly allocated to morphine and 16 to placebo; one infant assigned placebo was withdrawn from the study before monitoring began. The predefined stopping boundary was crossed, and trial recruitment stopped because of profound respiratory adverse effects of morphine without suggestion of analgesic efficacy. None of the co-primary outcome measures differed significantly between groups. PIPP-R score after retinopathy of prematurity screening was mean 11·1 (SD 3·2) with morphine and 10·5 (3·4) with placebo (mean difference 0·5, 95% CI −2·0 to 3·0; p=0·66). Noxious-evoked brain activity after heel lancing was median 0·99 (IQR 0·40–1·56) with morphine and 0·75 (0·33–1·22) with placebo (median difference 0·25, 95% CI −0·16 to 0·80; p=0·25). Administration of oral morphine (100 μg/kg) to non-ventilated premature infants has the potential for harm without analgesic efficacy. We do not recommend oral morphine for retinopathy of prematurity screening and strongly advise caution if considering its use for other acute painful procedures in non-ventilated premature infants. Wellcome Trust and National Institute for Health Research.

Erector spinae plane (ESP) block is a novel regional anesthesia technique and gaining importance for postoperative pain management. Since it was first described, the clinicians wonder if this new simple technique can replace paravertebral block (PVB). We aimed to compare the postoperative analgesic effect of ESP block and PVB with a control group in breast surgeries. Randomized controlled trial. Operating room. Seventy-five ASA I–II patients aged 25–65, who were scheduled to go under elective unilateral breast surgery for breast cancer were included to the study. Patients were randomized into three groups as ESP, PVB, and Control group. Ultrasound (US) guided ESP block and PVB with 20 ml 0.25% bupivacaine was done preoperatively to the patients according to their groups. All patients were provided with iv patient-controlled analgesia device for postoperative analgesia. Morphine consumptions and numeric rating scale (NRS) scores for pain were recorded at 1st, 6th, 12th and 24th hours postoperatively. There was a statistically significant difference between ESP and Control groups (p < 0,001) and between PVB and Control groups (p < 0,001), while there was no difference between ESP and PVB groups (p > 0,05) for 24-hour morphine consumptions. There was a significant difference between PVB and Control groups for NRS at postoperative 1st and 6th hour (p = 0.018 and p = 0.027 respectively). This study has shown that US guided ESP block and PVB provided adequate analgesia in patients undergoing breast surgery and have an opioid sparing effect by reducing morphine consumption. Clinical Trials Registry: NCT03480958. •ESP block provides effective analgesia in breast surgery.•ESP block has lower risk of complications compared to TPV block.•Both ESP block and TPV block have a similar analgesic effect in breast surgery.

Most people addicted to opioids began taking them because they were legally prescribed. Little attention has been paid to changing physicians' prescribing behavior. Using a randomized controlled trial format, Doctor et al. monitored the effect of notifying physicians who had a patient die of opioid overdose within 12 months of a prescription. The physicians received an injunction to prescribe safely from their county's medical examiner. This intervention led to reductions in high-intensity prescribing, reductions in the likelihood that an opioid-naïve patient received a prescription, and a reduction in overall cumulative opioid intake. Science , this issue p. 588 Feedback about a patient’s overdose may instill safe opioid prescribing habits in physicians. Most opioid prescription deaths occur among people with common conditions for which prescribing risks outweigh benefits. General psychological insights offer an explanation: People may judge risk to be low without available personal experiences, may be less careful than expected when not observed, and may falter without an injunction from authority. To test these hypotheses, we conducted a randomized trial of 861 clinicians prescribing to 170 persons who subsequently suffered fatal overdoses. Clinicians in the intervention group received notification of their patients’ deaths and a safe prescribing injunction from their county’s medical examiner, whereas physicians in the control group did not. Milligram morphine equivalents in prescriptions filled by patients of letter recipients versus controls decreased by 9.7% (95% confidence interval: 6.2 to 13.2%; P < 0.001) over 3 months after intervention. We also observed both fewer opioid initiates and fewer high-dose opioid prescriptions by letter recipients.

Adequate pain control is essential; however, acute pain is often undertreated in prehospital care. This study aimed to evaluate three analgesic regimens for treating acute pain in an ambulance setting. PreMeFen is a randomised, open-label, non-inferiority, three-arm, phase 3 trial conducted in the working areas of the ground ambulance service of the Innlandet Hospital Trust, Norway. Patients aged 18–69 years and 70 years and older with traumatic or medical acute pain scoring 4 or higher on the Numeric Rating Scale (NRS) were randomly assigned (1:1:1) to receive in titration doses 3 mL inhalational methoxyflurane, 50 μg or 100 μg intranasal fentanyl, or 0·05 mg/kg or 0·1 mg/kg intravenous morphine, respectively, depending on the age group. The primary endpoint was change in pain NRS score from baseline to 10 min after treatment start and was analysed per protocol. The non-inferiority margin was 1·3. This trial is registered with ClinicalTrials.gov (NCT05137184) and is completed. Between Nov 12, 2021, and April 22, 2023, 632 patients were assessed for eligibility, and 338 were randomly assigned to methoxyflurane (n=112), fentanyl (n=115), or morphine (n=111). 281 patients were included in the per-protocol population. 145 (52%) of 281 patients were female and 136 (48%) were male. Median age was 61 years (IQR 47–75). The baseline NRS score was 7·6 (SD 1·8). Mean NRS score changes after 10 min were –3·31 (SD 2·67) for methoxyflurane, –1·98 (2·28) for fentanyl, and –2·74 (2·12) for morphine. Comparing changes in mean NRS score while adjusting for baseline showed that methoxyflurane was non-inferior to fentanyl (–1·33 [95% CI –2·01 to –0·64]) and morphine (–0·36 [–1·03 to 0·31]). Intranasal fentanyl was not non-inferior to morphine at 10 min (0·91 [0·27 to 1·55]). Adverse events occurred in 26 (24%) of 109 patients in the morphine group, 27 (24%) of 112 in the fentanyl group, and 24 (22%) of 111 in the methoxyflurane group. Two serious adverse events, respiratory depression (grade 2) and loss of consciousness (grade 3), occurred in the same patient in the methoxyflurane group. There were no treatment-related deaths. Inhalational methoxyflurane is non-inferior to intranasal fentanyl and intravenous morphine for acute pain management in the prehospital environment, assessed 10 min after administration. Inhalational methoxyflurane serves as a valuable non-intravenous alternative in the early phase of treatment and might bridge the gap to longer-acting analgesics. Norwegian Air Ambulance Foundation and Innlandet Hospital Trust.

Background and ObjectivesThe role of a fascia iliaca compartment block (FICB) for postoperative analgesia after total hip arthroplasty (THA) remains questionable. High-dose local anesthetics and a proximal injection site may be essential for successful analgesia. High-dose local anesthetics may pose a risk for local anesthetic systemic toxicity. We hypothesized that a high-dose longitudinal supra-inguinal FICB is safe and decreases postoperative morphine consumption after anterior approach THA.MethodsWe conducted a prospective, double blind, randomized controlled trial. Patients scheduled for THA were randomized to group FICB (longitudinal supra-inguinal FICB with 40-mL ropivacaine 0.5%) or group C (control, no block). Standard hypothesis tests (t test or Mann-Whitney U test, χ2 test) were performed to analyze baseline characteristics and outcome parameters. The primary end point of the study was total morphine (mg) consumption at 24 hours postoperatively. Serial total and free ropivacaine serum levels were determined in 10 patients.ResultsAfter obtaining ethical committee approval and written informed consent, 88 patients were included. Mean (SD) morphine consumption at 24 hours postoperatively was reduced in group FICB compared to group C: 10.25 (1.64) mg versus 19.0 (2.4) mg (P = 0.004). Using a mean dose of 2.6-mg/kg ropivacaine (range, 2–3.4 mg/kg), none of the patients had total or free ropivacaine levels above the maximum tolerated serum concentration.ConclusionsWe conclude that a high-dose longitudinal supra-inguinal FICB reduces postoperative morphine requirements after anterior approach THA.Clinical Trials Registry: EU Clinical Trials Register. www.clinicaltrialsregister.eu #2014-002122-12.

Background To determine whether intermittent intravenous (IV) paracetamol as primary analgesic would significantly reduce morphine consumption in children aged 0–3 years after cardiac surgery with cardiopulmonary bypass. Methods Multi-center, randomized, double-blinded, controlled trial in four level-3 Pediatric Intensive Care Units (PICU) in the Netherlands and Belgium. Inclusion period; March 2016–July 2020. Children aged 0–3 years, undergoing cardiac surgery with cardiopulmonary bypass were eligible. Patients were randomized to continuous morphine or intermittent IV paracetamol as primary analgesic after a loading dose of 100 mcg/kg morphine was administered at the end of surgery. Rescue morphine was given if numeric rating scale (NRS) pain scores exceeded predetermined cutoff values. Primary outcome was median weight-adjusted cumulative morphine dose in mcg/kg in the first 48 h postoperative. For the comparison of the primary outcome between groups, the nonparametric Van Elteren test with stratification by center was used. For comparison of the proportion of patients with one or more NRS pain scores of 4 and higher between the two groups, a non-inferiority analysis was performed using a non-inferiority margin of 20%. Results In total, 828 were screened and finally 208 patients were included; parents of 315 patients did not give consent and 305 were excluded for various reasons. Fourteen of the enrolled 208 children were withdrawn from the study before start of study medication leaving 194 patients for final analysis. One hundred and two patients received intermittent IV paracetamol, 106 received continuous morphine. The median weight-adjusted cumulative morphine consumption in the first 48 h postoperative in the IV paracetamol group was 5 times lower (79%) than that in the morphine group (median, 145.0 (IQR, 115.0–432.5) mcg/kg vs 692.6 (IQR, 532.7–856.1) mcg/kg; P  <  0.001 ). The rescue morphine consumption was similar between the groups (p = 0.38). Non-inferiority of IV paracetamol administration in terms of NRS pain scores was proven; difference in proportion − 3.1% (95% CI − 16.6–10.3%). Conclusions In children aged 0–3 years undergoing cardiac surgery, use of intermittent IV paracetamol reduces the median weight-adjusted cumulative morphine consumption in the first 48 h after surgery by 79% with equal pain relief showing equipoise for IV paracetamol as primary analgesic. Trial Registration Clinicaltrials.gov, Identifier: NCT05853263; EudraCT Number: 2015-001835-20.

In this trial comparing methadone with buprenorphine in opioid-dependent pregnant women, neonates exposed to buprenorphine required less morphine to treat neonatal abstinence syndrome (NAS) and had a significantly shorter duration of hospitalization and of treatment for NAS. Opioid dependence during pregnancy is compounded by multiple risk factors contributing to adverse maternal, neonatal, and long-term developmental consequences. 1 – 6 Improved treatment options should reduce the public health and medical costs associated with the treatment of neonates exposed to opioids, which in 2009 was estimated at $70.6 million to $112.6 million in the United States alone. 7 Just as the use of methadone in nonpregnant patients with opioid dependence improves patient outcomes, 8 its use as part of a comprehensive approach to the care of pregnant women improves maternal and neonatal outcomes, as compared with no treatment and with medication-assisted withdrawal. 4 , . . .

Recent evidence has shown that vitamin C has analgesic and opioid sparing properties in immediate postoperative context. However, this has never been studied for acute musculoskeletal (MSK) emergency department (ED) injuries. The aim of this pilot study is to evaluate the feasibility of conducting a randomized placebo-controlled study to determine the opioid sparing and analgesic effect of vitamin C compared to placebo, in acute MSK injured ED patients. A double-blind randomized controlled trial (RCT) distributed in two arms, stratified for fractures, was performed in a tertiary care center, one group receiving 1 g of vitamin C twice a day for 14 days and another receiving placebo. Participants were ≥18 years of age, treated in ED for MSK injuries present for ≤2 weeks, and discharged with a standardized opioid prescription of 20 morphine 5 mg tablets (M5T) and, at the clinician discretion, 28 tablets of naproxen 500 mg. Participants completed a 14-day paper diary and were contacted by phone at 14 days, to document their analgesic use, vitamin C consumption, and pain intensity. Overall, 137 patients were screened; 44(32%) were excluded, 38(40.9%) refused, leaving 55(59.1%) participants, with a consent rate of 9.2/month. Mean age was 53 years (SD = 16) and 55% were men. Fourteen (25%) participants were lost to follow-up and 33(83%) patients complied with treatment. For per-protocol analysis, the median (IQR) M5T consumed was 6.5 (3.3-19.5) for the vitamin C and 9.0 (1.5-16.0) for placebo group. The median (IQR) naproxen 500 mg tablets consumed was 0 (0-9.8) for the vitamin C group and 20 (0-27) for the placebo arm. This pilot study supports the feasibility of a larger RCT on the opioid sparing and analgesic properties of vitamin C for acute MSK injured ED patients. Strategies to reduce the refusal and lost to follow-up rates are discussed. NCT05555576, ClinicalTrials.Gov PRS.

BackgroundUltrasound-guided (USG) erector-spinae plane block (ESPB) may be better than intravenous opioids in treating acute hepatopancreaticobiliary (HPB) pain in the ED.MethodsThis open-label randomised controlled trial was conducted in the ED of a tertiary-care hospital between March and August 2023. All adult patients with severe HPB pain were recruited during times that a primary investigator was present. Unconsenting patients, numeric rating scale (NRS) ≤6, age ≤18 and ≥80 years, pregnant, unstable or with allergies to local anaesthetics or opioids were excluded. Patients in the intervention arm received bilateral USG ESPB with 0.2% ropivacaine at T7 level, by a trained ED consultant, and those in the control arm received 0.1 mg/kg intravenous morphine. Pain on a 10-point NRS was assessed by the investigators at presentation and at 1, 3, 5 and 10 hours after intervention by the treatment team, along with rescue analgesia requirements and patient satisfaction. Difference in NRS was analysed using analysis of co-variance (ANCOVA) and t-tests.Results70 participants were enrolled, 35 in each arm. Mean age was 40.4±13.2 years, mean NRS at presentation in the intervention arm was 8.0±0.9 and 7.6±0.6 in the control arm. NRS at 1 hour was significantly lower in the ESPB group (ANCOVA p<0.001). At 1, 3, 5 and 10 hours, reduction of NRS in the intervention arm (7±1.6, 6.7±1.9, 6.6±1.8, 6.1±1.9) was significantly greater than the control arm (4.4±2, 4.6±1.8, 3.7±2.2, 3.8±1.8) (t-test, p<0.001). Fewer patients receiving ESPB required rescue analgesia at 5 (t-test, p=0.031) and 10 hours (t-test, p=0.04). More patients were ‘very satisfied’ with ESPB compared with receiving only morphine at each time period (p<0.001).ConclusionESPB is a promising alternative to morphine in those with HPB pain.Trial registration numberCTRI/2023/03/050595.