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HSK21542, a peripherally restricted kappa opioid receptor agonist, was evaluated for efficacy and safety in patients with postoperative pain following abdominal surgery. This was assessed in two phase 3, multicentre, randomized, double-blind, controlled trials (HSK21542-301 [ClinicalTrials.gov identifier, NCT04738357] and HSK21542-303 [ClinicalTrials.gov identifier, NCT05390905]) in China. HSK21542-301 was a dual-arm study comparing HSK21542 1.0 μg/kg with placebo, while HSK21542-303 involved three arms comparing HSK21542 1.0 μg/kg with tramadol 50 mg/dose and placebo. All treatments were administered intravenously. The primary endpoint was the time-weighted summed pain intensity differences over 24 h (SPID 0-24 h ). Both HSK21542-301 (least squares [LS] mean [± standard error], −39.1 [1.88] vs −27.4 [1.89]; P  < 0.001) and HSK21542-303 (−64.0 [2.25] vs −45.9 [2.25]; P  < 0.001) demonstrated superiority of HSK21542 over placebo in terms of SPID 0-24 h , while HSK21542-303 showed non-inferiority to tramadol (LS mean difference, −1.1; 95% confidence interval, −7.4 to 5.1; P  < 0.001). Furthermore, HSK21542 had a comparable safety profile to placebo, inducing fewer gastrointestinal adverse events compared with tramadol. Grade ≥3 treatment-emergent adverse events occurred in eight (5.9%) and three (2.3%) patients in the HSK21542 arm of HSK21542-301 and HSK21542-303, respectively. In conclusion, HSK21542 showed potent analgesic effect and was well tolerated in patients who underwent abdominal surgery and experienced postoperative pain. Commonly used opioids for pain management primarily target the mu opioid receptor. However, mu opioid receptor agonists often come with harmful side effects. Here, the authors report the results of two phase 3 trials of HSK21542 (anrikefon), a highly selective activator of peripheral kappa opioid receptor agonists, for postoperative pain treatment following abdominal surgery.

Laparoscopic cholecystectomy (LC) is a frequently applied minimally invasive surgery. Intraoperative access is provided with small keyhole entries on the abdominal wall. However, LC causes moderate to severe postoperative pain. The subcostal approach of TAP block was described by Hebbard et al. for postoperative analgesia especially for upper abdominal surgeries. Ultrasound-guided erector spinae plane (US-ESP) block is a novel technique targeting ventral rami, dorsal rami and rami communicantes of the spinal nerves. Single-blinded, prospective, randomized study. Tertiary university hospital, postoperative recovery room and surgical ward. Seventy-six patients (ASA I-II) were divided into two equal groups. After applying the exclusion criteria, 68 patients were included in final analysis (34 patients in ESP group and 34 in OSTAP group). Erector spinae plane block was performed in the ESP group and oblique subcostal transversus abdominis block was performed in the OSTAP group. Measurements: Postoperative tramadol consumption and pain scores between groups were compared. In addition, intraoperative fentanyl need was measured. Postoperative tramadol consumption was 139.1 ± 21.9 mg in the ESP group and 199.4 ± 27.7 mg in the OSTAP group (mean difference 60.29 mg, 95% confidence interval - 72.40 to - 48.19; p < 0.001). NRS scores at almost all time-points were lower in the ESP group according to the repeated measures analysis. Integration of AUC and Mann Whitney U test results have revealed that there was no time wise difference between ESP and OSTAP groups even though NRS scores by itself and time-wise linear area under curve scores were higher in the OSTAP group compare to ESP group. There were no differences in intraoperative fentanyl need. Ultrasound-guided ESP block reduced postoperative tramadol consumption and pain scores more effectively than OSTAP block after laparoscopic cholecystectomy surgery. •Laparoscopic cholecystectomy causes moderate to severe postoperative pain.•OSTAP block provides analgesia especially for upper abdominal surgeries.•ESP is a novel block which extends cranially and caudally over several dermatomal levels.•Both ESP and OSTAP blocks are effective for analgesia after cholecystectomy.

Background The aim of this prospective, randomized, controlled study was to evaluate the effect of ultrasound (US)-guided bilateral erector spinae plane (ESP) block on postoperative opioid consumption and respiratory recovery in patients with obesity undergoing laparoscopic sleeve gastrectomy (LSG). Methods The study was conducted on 40 patients scheduled for LSG. The patients were randomly allocated into either the ESP block group or the control group. The US-guided bilateral ESP block was performed preoperatively. The control group received no intervention. Results Postoperative median [IQR] tramadol consumption was significantly lower in the ESP block group [150.0 [100–200] mg vs 450.0 [400–500] mg, p  < 0.0001]. Postoperative spirometric variables were significantly impaired in both groups, compared with preoperative variables ( p  < 0.0001). Intraoperative median [IQR] fentanyl consumption was 200.0 [200–200] µg in the ESP block group, and 350.0 [300–400] µg in the control group ( p  < 0.0001). Postoperative mean pain scores at rest and during movement were significantly lower in the ESP block group, at all time points ( p  < 0.05). In terms of mean arterial PH, Horowitz ratio, and PaCO 2 , there was no statistically significant difference between the groups ( p  > 0.05). None of the patients experienced postoperative respiratory adverse events and/or block-related complications. Conclusions US-guided bilateral ESP block significantly reduced both intraoperative and postoperative analgesic consumptions and provided effective postoperative pain control for patients with obesity undergoing bariatric surgery. Following bariatric surgery, all patients’ postoperative pulmonary functions deteriorated. The effect of US-guided bilateral ESP block on postoperative respiratory recovery could not be clearly demonstrated. Randomized controlled studies with a larger patient population are necessary.

This trial aimed to identify the effects of providing pharmacogenomic (PGx) results and recommendations for patients with chronic pain treated in primary care practices compared to standard care. An open‐label, prospective, largely virtual, type‐2 hybrid effectiveness trial randomized participants to PGx or standard care arms. Adults with pain ≥ 3 months who were treated with tramadol, codeine, or hydrocodone enrolled. Alternative analgesics were recommended for CYP2D6 intermediate or poor metabolizers (IM/PMs). Prescribing decisions were at providers' discretion. The trial randomized 253 participants. A modified intent‐to‐treat primary analysis assessed change in pain intensity over 3 months among IM/PMs (PGx: 49; Standard care: 57). The PGx and standard care arms showed no difference in pain intensity change (−0.10 ± 0.63 vs. −0.21 ± 0.75 standard deviation; p = 0.74) or PGx‐aligned care (69% vs. 63%; standardized difference [SD] = 0.13). In IM/PMs, secondary analyses of pain intensity change suggested improvements with PGx‐aligned (n = 70; −0.21 ± 0.70) vs. unaligned care (n = 36; −0.06 ± 0.69) (SD = −0.22), with this difference increasing when examining IM/PMs with an analgesic change (aligned: n = 31, −0.28 ± 0.76; unaligned: n = 36, −0.06 ± 0.69; SD = −0.31). This approach to PGx implementation for chronic pain was not associated with different prescribing (i.e., similar proportions of PGx‐aligned care) or clinical outcomes. Secondary analyses suggest that prescribing aligned with PGx recommendations showed a small improvement in pain intensity. However, the proportion of patients with a clinically meaningful improvement (≥ 30%) in pain intensity was similar. Future efforts should identify effective implementation methods.

Serratus anterior plane block (SAPB) was evaluated that in patients with the complaint of rib fracture pain in terms of total analgesic consumption and pain scores. Sixty patients with rib fracture and NRS (Numeric Rating Scala) pain scores equal or greater than four were included in randomized controlled study. Patients were randomized to perform SAPB or control group. Primary outcome was total tramadol consumption in 24 h. Secondary outcomes were NRS scores (after Patient Controlled Analgesia (PCA) application 30 min, first, second, 4 th, 6 th, 12 th, 24 th hour), peripheral oxygen saturation (first and 24 th hour after PCA application), chronic pain. and complications. The total tramadol consumption significantly lower in group S (p = 0.02). NRS scores after 30 min, 1 h, 2 h, 4 h, 6 h, 12 h, and 24 h were significantly lower in group S than in group C (p < 0.001, p < 0.001, p < 0.001, p < 0.001, p = 0.002, p = 0.026). The total number of patients who reported of chronic pain at rest and during effort was significantly lower in group SAPB than in group C (p = 0.006). Nine patients in group C were reported of pain, four of whom had pain at rest and five had pain during effort. One patient in group S was reported of pain during effort. This study demonstrated that SAPB, as part of multimodal analgesia in pain management due to rib fractures, is safe and effective in reducing acute pain. •Serratus anterior plane block (SAPB) is safe and effective for rib fracture pain.•Nowadays fascial plane blocks are very popular.•SAPB is an easy application.

IntroductionIntensive care unit (ICU) patients under mechanical ventilation experience mild-to-severe pain. International guidelines emphasise the importance and benefits of multimodal analgesia to minimise opioid consumption and its side effects. However, no recommendation about drugs or protocol has been formulated. The aim of the Opioid-Free Analgesia in Intensive Care Unit study is to assess the feasibility of a standardised multimodal analgesia strategy and its benefits following the impact of remifentanil sparing in ICU patients.Methods and analysis50 mechanically ventilated adult patients will be recruited in a randomised, placebo-controlled, double-blind, feasibility trial. In the interventional group, patients will receive a standardised multimodal analgesia, initially receiving nefopam and tramadol, implementing with ketamine if patients remain painful, and then implementing with remifentanil with escalating doses in case of insufficient analgesia. In the control group, patients will receive remifentanil, implementing doses gradually to achieve analgesia. The primary outcome will be the daily consumption of remifentanil between the 24th and 48th hour after inclusion. Secondary outcomes will include drug tolerance, mechanical ventilation duration, ICU and hospital length of stay, 28-day and 90-day mortalities and 90-day opioid consumption.Ethics and disseminationThe study protocol was accepted by the Nîmes University Hospital’s research committee, the French ethics committee (Institutional Review Board OUEST IV) and the French National Agency for the Safety of Medicines and Health Products (ANSM).Trial registration numberClinicalTrials.gov: NCT05825560

Background and Objectives New acute pain medications are needed that provide effective analgesia while minimizing side effects and opioid exposure. Clinical trials of co-crystal of tramadol-celecoxib (CTC) have demonstrated an improved benefit/risk profile versus tramadol or celecoxib alone. We pooled data from two phase 3 clinical trials to evaluate the efficacy of CTC 200 mg twice daily (BID) in acute moderate-to-severe pain. Methods Efficacy data were pooled from STARDOM1 [acute pain following oral surgery (NCT02982161)] and ESTEVE-SUSA-301 [acute pain following bunionectomy (NCT03108482)]. The primary efficacy outcome was sum of pain intensity difference from 0 to 48 h (SPID 0–48 ). Results A total of 344 patients received CTC 200 mg BID, 342 received tramadol 50 or 100 mg four times a day, 181 received celecoxib 100 mg BID, and 172 received placebo. The least-squares mean difference in SPID 0–48 was −21.8 ( p = 0.002) for CTC versus tramadol and −72.8 ( p < 0.001) for CTC versus placebo. A similar pattern of SPID 0–48 was observed with CTC versus comparator whether patients had moderate or severe pain at baseline. Reduction in pain intensity was faster and reached mild intensity earlier with CTC versus comparators. Patients were significantly ( p ≤ 0.005) less likely to receive rescue medication within 4 or 48 h with CTC compared with tramadol or placebo. Conclusions This pooled analysis reinforces the efficacy profile of CTC versus tramadol and, given that CTC permits lower daily tramadol dosing and thereby reduces unnecessary opioid use, this highlights its improved benefit/risk profile and its potential for the management of moderate-to-severe pain.

Background Postoperative pain is a significant challenge in oral surgery. Tramadol exhibits both systemic and local analgesic effects, with proven efficacy in combination with local anesthetics. Purpose This study evaluated the efficacy of local anesthetics combined with tramadol in reducing pain and analgesic use after third molar surgery. Study design, setting, sample This randomized, double-blind trial included ASA I–II patients aged 18–50 years and weighing 70–80 kg who were undergoing impacted third molar surgery. Patients requiring extra anesthesia, those with tramadol hypersensitivity, or those who recently used sedatives were excluded. Independent variables Two local anesthetic solutions were compared: the LT group (tramadol and articaine with epinephrine) and the LA group (articaine with epinephrine, control). Main outcome variable Postoperative pain was measured as the primary outcome via a visual analog scale (VAS) at multiple time points (10 min and 1, 2, 4, 6, 12, 24 and 48 h postsurgery). The secondary outcomes included the timing of the first analgesic intake and the total number of analgesic doses consumed within 48 h. Covariates The covariates included age, sex, BMI, surgical duration, and adverse effects (nausea, vomiting, burning). Analyses Age and surgical duration were analyzed with t tests; VAS scores and analgesic use were analyzed with Mann–Whitney U tests; and categorical data were analyzed with Fisher’s exact test or Yates’ correction ( p  < 0.01). Results Sixty patients were randomized into the LT ( n  = 30) and LA ( n  = 30) groups. Age, sex, and BMI distributions were similar between the groups. VAS pain scores were lower in the LT group at 1, 2, and 6 h (mean difference: -4.9, -1.9, and − 1.4; p  < 0.01) but higher at 4 h (mean difference: 1.5; p  < 0.01). The LT group required their first analgesic later (5.2 ± 0.8 vs. 2.0 ± 0.6 h; mean difference: 3.1; p  < 0.01) and consumed fewer analgesics (1.8 ± 0.5 vs. 3.6 ± 0.8 doses; mean difference: -1.8; p  < 0.01). A transient higher VAS score was observed at 4 h in the LT group, likely reflecting delayed analgesic use. Adverse effects were minimal and not significantly different between groups. Conclusion and relevance Local anesthetics combined with tramadol reduce pain and analgesic use after third molar surgery. This strategy improves recovery and warrants further research for broader applications. Trial registration ClinicalTrials.gov NCT05614440, Date of registration 14 November 2022.

Purpose The objective of this study was to examine the hypothesis that the opioid consumption of patients who receive a rhomboid intercostal block (RIB) or a pectoral nerve (PECS) block after unilateral modified radical mastectomy (MRM) surgery is less than that of patients who receive local anesthetic infiltration. Methods Eighty-one female patients aged 18–70 years who underwent unilateral MRM surgery with general anesthesia were randomly allocated to three groups. The first group received an RIB with 30 ml of 0.25% bupivacaine on completion of the surgery, and the second received a PECS block with the same volume and concentration of local anesthetic. In the third (control) group, local infiltration was applied to the wound site with 30 ml of 0.25% bupivacaine at the end of the surgery. The patients’ total tramadol consumption, quality of recovery (QoR), postoperative pain scores, and sleep quality were evaluated in the first 24 h postoperatively. Results Both the RIB (58.3 ± 22.8 mg) and PECS (68.3 ± 21.2 mg) groups had significantly lower tramadol consumption compared to the control group (92.5 ± 25.6 mg) ( p  < 0.001 and p  = 0.002, respectively). Higher QoR scores were observed in the RIB and PECS groups than the control group at 6 h post-surgery. The lowest pain values were observed in the RIB group. The sleep quality of the patients in the RIB and PECS groups was better than that of the control group ( p  < 0.001). Conclusion Compared to local anesthetic infiltration, the RIB and PECS blocks applied as part of multimodal analgesia in MRM surgery reduced opioid consumption in the first 24 h and improved the quality of recovery in the early period.

Background Age-related changes in the concentration–effect relationship of (+)- O -desmethyl-tramadol [(+)-ODM], tramadol’s active metabolite, are not documented in the elderly. Objective The objective of this study was to characterize, in elderly and young subjects, the (+)-ODM pharmacokinetic and pharmacodynamic relationship to examine the effect of age after single-dose administration of tramadol 200 mg extended-release tablets. Methods A population analysis of a double-blind, randomized, placebo-controlled, two-period cross-over study including 13 elderly (aged ≥75 years) subjects with mild renal insufficiency and 16 young (aged 18–40 years) subjects was conducted. For 48 h post-dose, blood samples were collected and pain tolerance thresholds measured using an electrically stimulated pain model. A pharmacokinetic/pharmacodynamic model incorporating a one-compartment pharmacokinetic model for (+)-ODM parameterized with first-order formation rate, clearance (CL/ f m ), volume of distribution ( V / f m ) and a sigmoid maximum effect ( E max ) model incorporating baseline ( E 0 ) and placebo effect was used. Results Maximum plasma concentrations of (+)-ODM occurred later and plasma concentrations declined more slowly in the elderly than in young subjects. In the elderly, V / f m was 76% larger and CL/ f m 16% slower. Baseline ( E 0 ) and sensitivity ( C 50 ) for pain tolerance were similar between young and elderly subjects. However, the E max parameter was 2.5 times higher in the elderly and maximum possible treatment-related effect was 169 (135–221) in the young and 194 (149–252) in the elderly; that is, 15% higher in the elderly. Conclusions This exploratory analysis suggests that age-related differences exist in the distribution and elimination of (+)-ODM, including a 76% larger distribution outside the central compartment and 16% slower clearance of (+)-ODM. These pharmacokinetic changes are associated with a 15% higher maximum possible treatment-related effect and carry the potential for greater efficacy but also the potential for increased side effects at the same dose in elderly subjects. Clinicaltrials.gov identifier: NCT02329561.