Fentanyl and xylazine crisis:Crafting coherent strategies for opioid overdose prevention

The United States is in the throes of a severe opioid overdose epidemic,primarily fueled by the pervasive use of fentanyl and the emerging threat of xylazine,a veterinary sedative often mixed with fentanyl.The high potency and long duration of fentanyl is compounded by the added risks from xylazine,heightening the lethal danger faced by opioid users.Measures such as enhanced surveillance,public awareness campaigns,and the distribution of fentanylxylazine test kits,and naloxone have been undertaken to mitigate this crisis.Fentanyl-related overdose deaths persist despite these efforts,partly due to inconsistent policies across states and resistance towards adopting harm reduction strategies.A multifaceted approach is imperative in effectively combating the opioid overdose epidemic.This approach should include expansion of treatment access,broadening the availability of medications for opioid use disorder,implementation of harm reduction strategies,and enaction of legislative reforms and diminishing stigma associated with opioid use disorder.

Randomized Double-Blind Controlled Clinical Study of Ciprofol and Propofol in Patients with Painless Artificial Abortion

Background and Objectives: Propofol is a commonly used intravenous anesthetic for painless artificial abortion, but the injection pain and related adverse reactions such as those related to respiration and circulation it induces have also been criticized. We aimed to conduct a comparative study on the efficacy, safety and comfort of ciprofol and propofol applied in painless artificial abortion. Materials and Methods: A total of 140 early pregnant patients undergoing painless induced abortion were selected and randomly divided into the ciprofol combined with fentanyl group (Group C) and the propofol combined with fentanyl group (Group P), with 70 cases in each group. The anesthetic effect, depth of anesthesia sedation (NI), onset time, recovery time, recovery time of orientation, retention time in the anesthesia recovery room and total amount of intravenous anesthetic drug were recorded in both groups. The respiratory rate (RR), oxygen saturation (SpO2), mean arterial pressure (MAP), and heart rate (HR) at different time points were recorded. The occurrence of perioperative adverse events, injection pain, postoperative nausea and vomiting, and dizziness were compared. The pain score at 30 minutes after operation and the satisfaction of patients and surgeons with anesthesia were evaluated. Results: The success rate of anesthesia in both groups was 100%. There were no statistically significant differences in the NI value at each time point, intraoperative body movement, recovery time, recovery time of orientation, retention time in the anesthesia recovery room, and total dosage of sedative drugs (ml) between the two groups;the onset time in Group C was longer than that in Group P, with a statistically significant difference (P Conclusion: The efficacy of ciprofol in painless induced abortion is equivalent to that of propofol, and the incidence of adverse reactions is lower than that of propofol, with higher safety and comfort.

Comparison of Propofol and Fentanyl for Preventing Emergence Agitation Following Sevoflurane Anesthesia in Pediatric Patients: A Single-Center Study in Bangladesh

Background: Emergence agitation (EA) is a common phenomenon observed in pediatric patients following general anesthesia. This study aimed to assess the efficacy of propofol and fentanyl in preventing EA and to compare their associated complications or side effects. Methods: This prospective randomized observational comparative study was conducted at Dhaka Medical College Hospital from July 2013 to June 2014. The study aimed to evaluate the effects of propofol and fentanyl on EA in children aged 18 to 72 months undergoing circumcision, herniotomy, and polypectomy operations. Ninety children were included in the study, with 45 in each group. Patients with psychological or neurological disorders were excluded. Various parameters including age, sex, weight, American Society of Anesthesiologists (ASA) class, duration of anesthesia, Saturation of Peripheral Oxygen (SPO2), heart rate (HR), respiratory rate (RR), Pediatric Anesthesia Emergence Delirium (PAED) score, duration of post-anesthesia care unit (PACU) stay, incidence of laryngospasm, nausea, vomiting, and rescue drug requirement were compared between the two groups. Results: Age, sex, weight, ASA class, and duration of anesthesia were comparable between the two groups. Perioperative SpO2 and HR were similar in both groups. However, the PAED score was significantly higher in the fentanyl group during all follow-ups except at 30 minutes postoperatively. The mean duration of PACU stay was significantly longer in the fentanyl group. Although the incidence of laryngospasm was higher in the fentanyl group, it was not statistically significant. Conversely, nausea or vomiting was significantly higher in the fentanyl group. The requirement for rescue drugs was significantly higher in the fentanyl group compared to the propofol group. Conclusion: Both propofol and fentanyl were effective in preventing emergence agitation in pediatric patients undergoing various surgical procedures under sevoflurane anesthesia. However, propofol demonstrated a better safety profile with fewer incidences of nausea, vomiting, and rescue drug requirements compared to fentanyl.

Manner of Death and Fentanyl Related Drug Overdose Trends in Marion County, Indiana, US from 2018 to 2021

The purpose of this research was to investigate the manner of deaths in Marion County, throughout the years of 2018 to 2021 to see if there were any correlative increases in homicide, suicide, natural, accidental, or drug overdose related deaths. We surveyed the incidence of all deaths that occurred from 2018 through 2021 which came through the Marion County Coroner’s Office, Indiana. The data was then divided into two halves. According to the data, the leading manner of death in the first half and second half was accidental. This study revealed a total of 8732 cases: 3817 of them were observed to be accidental, 3092 natural, 956 homicide, 689 suicide, and 178 were undetermined. There were initially 318 drug overdose related deaths in 2018 and they increased to 2163 by 2021. In 2018, the number of deaths due to fentanyl related overdoses increased from 195 to 799 in 2021. This research will contribute to the forensic science field by providing information about the manner of death and fentanyl trends in Marion County over the last four years.

Transdermal Fentanyl for Management of Cancer Pain in Elderly Patients in China

Objective: Objective: To assess the effect and adverse effects of transdermal fentanyl for elderly patients with cancer pain in China. Methods: A total of 1664 elderly patients (aged 65-90 with mean age of 72.6) with cancer pain enrolled in the multicenter study from 136 institutes in China. Of them, 408 (28.8%) patients were 75 years old or older. All patients received transdermal fentanyl for the management of cancer pain. The patients were asked to record the attacks of pain, quality of life, and any side effects of the treatment. Results: Baseline mean of pain intensity was 7.34. On day 1, 3, 6, 9 15, and 30, the pain mean scores were decreased to 3.82, 2.80, 2.43, 2.11, 1.83, 1.64 (P=0.000). The effective rate was 97.18%. The mean doses of fentanyl was 31.34 g/h (25-150 g/h) initially, and 40.59 g/h and 47.50 g/h (25-200 g/h) at day 15 and day 30. At treatment day 15, the dose of fentanyl was ranger from 25 to 50 g/h in 91.8% of patients, 75 to 100 g/h in 7.5% patients, and 125 to 200 g/h only in 0.8% patients. The fine quality of life was in 25.4% patients before treatment, and was 71.15% and 73.04% at day 15 and day 30 respectively (P=0.0000). The common side effects were constipation (10.70%), nausea (11.96%), dizzy (6.85%), vomiting (3.85%), sedation (2.40%), Respiratory depression (0.12%). 86.2% patients preferred continue treated by transdermal fentanyl. Conclusions: Transdermal fentanyl for the elderly with cancer pain is effective, safe, convenient, and can improve the quality of life. Transdermal fentanyl can be recommended as a first-line drug for the treatment of elderly patients with moderate to severe cancer pain, and the initial doses is recommended as 25 g/h.

The Effect of Test Dose Fentanyl on Predicting Postoperative Respiratory Depression in Patients with Continuous Intravenous Morphine Analgesia

Objective: To evaluate the effect of test dose fentanyl on predictingpostoperative analgesia and respiratory depression. Methods: Preoperatively the lowest pulseoximeter saturation (SpO_2) under room air breathing was measured after 2 μg/kg of fentanyl givenintravenously in 35 patients who were scheduled with continuous intravenous morphine analgesia (12μg·kg^(-1)·h^(-1)) postoperatively. Results: The test dose fentanyl resulted in respiratorydepression in 19 of 35 cases, while 8 (42.1%) of the 19 cases developed respiratory depressionpostoperatively. However in the rest 16 patients, no patient (0) developed respiratory depression (P< 0.01). The fentanyl-induced lowest SpO_2 significantly correlated with the lowest SpO_2postoperatively (P < 0.01). The analgesia effect in terms of verbal analogue scale was correlatedneither with the fentanyl-induced lowest SpO_2 nor with the lowest SpO_2 postoperatively (P > 0.05).Conclusion: The patient who was sensitive to fentanyl-induced respiratory depression would take ahigh risk to develop postoperative respiratory depression with intravenous morphine analgesia andthe patient with respiratory depression does not always go with satisfactory analgesia.

4-取代Fentanyl类化合物电子结构及构效关系研究

本文对十一个4-取代Fentanyl类化合物进行了量子化学(INDO)计算,研究了它们的电子结构及构效关系.结果表明,这些化合物同其他Fentanyl类化合物在主要活性部位和电子结构趋势上基本相同.酰胺氧原子是最重要的负电中心,哌啶氮原子在季铵化后发挥正电中心作用.4-取代基的极性基团可能以电荷转移作用或氢键接受体形式与受体极性部位结合,并能影响其他活性部位电子密度,另外,4-取代基的立体因素与疏水因素同生物活性相关.

APPLICATION OF LORNOXICAM TO PATIENT-CONTROLLED ANALGESIA IN PATIENTS UNDERGOING ABDOMINAL SURGERIES

Objective To assess the efficacy and safety of lornoxicam, one non-steroidal anti-inflammatory drug (NSAID) in patient-controlled analgesia (PCA) in patients undergoing abdominal surgeries. Methods Thirty-nine patients scheduled for abdominal surgeries were randomly assigned to different PCA treatment groups using either lornoxicam or fentanyl postoperatively. Pain intensity difference (PID) and sum of pain intensity difference (SPID) were used to assess the analgesic efficacy of both drugs during a 24-hour period. Results The analgesic efficacy of lornoxicam is 1/66 of fentanyl, which was shown by SPID value of 3.250 and 3.058, respectively (P > 0.05). Lornoxicam caused fewer adverse events than fentanyl (33% vs. 68%, P < 0.05). Conclusion In clinic, we can use lornoxicam to treat postoperative pain effectively and with less adverse reactions com-pared with fentanyl.

Fentanyl inhibits glucose-stimulated insulin release from β-cells in rat pancreatic islets

AIM： TO explore the effects of fentanyl on insulin release from freshly isolated rat pancreatic islets in static culture. METHODS： Islets were isolated from the pancreas of mature Sprague Dawley rats by common bile duct intraductal collagenase V digestion and were purified by discontinuous Ficoll density gradient centrifugation. The islets were divided into four groups according to the fentanyl concentration： control group （0 ng/mL）, group I （0.3 ng/mL）, group I （3.0 ng/mL）, and group III （30 ng/mL）. In each group, the islets were co-cultured for 48 h with drugs under static conditions with fentanyl alone, fentanyl ＋ 0.1 μg/mL naloxone or fentanyl ＋ 1.0 μg/mL naloxone. Cell viability was assessed by the MTT assay. Insulin release in response to low and high concentrations （2.8 mmol/L and 16.7 mmol/L, respectively） of glucose was investigated and electron microscopy morphological assessment was performed. RESULTS： Low- and high-glucose-stimulated insulin release in the control group was significantly higher than in groups I and II （62.33 ± 9.67 μIU vs 47.75 ± 8.47 μIU, 39.67 ± 6.18 μIU and 125.5 ± 22.04 μIU vs 96.17 ± 14.17 μIU, 75.17 ± 13.57 μIU, respectively, P 〈 0.01） and was lowest in group III （P 〈 0.01）. After adding 1 μg/mL naloxone, insulin release in groups II and II was not different from the control group. Electron microscopy studies showed that the islets were damaged by 30 ng/ml fentanyl. CONCLUSION： Fentanyl inhibited glucose-stimulated insulin release from rat islets, which could be prevented by naloxone. Higher concentrations of fentanyl significantly damaged β-cells of rat islets.

Effects of Morphine,Fentanyl and Tramadol on Human Immune Response

Summary： Morphine has been reported to suppress human immune response. We aimed to observe the effects of morphine, fentanyl and tramadol on NF- K B and IL-2 from both laboratory and clinical perspective. Jurkat cells were incubated with ten times clinically relevant concentrations of morphine, fentanyl and tramadol before being stimulated with PMA. NF- κB binding activity and IL-2 levels were measured, In the clinical study, 150 consenting patients were randomized into 3 groups according to the analgesics used in them, namely, group morphine （M）, group fentanyl （F） and group tramadol （T）. IL-2 was measured preoperatively and 1, 3 and 24 h after operation. Consequently, NF-κB activation was suppressed by morphine and fentanyl but not by tramadol. IL-2 was significantly decreased by morphine and fentanyl but not by tramadol in vitro. In the PCA patients, IL-2 was decreased in group M and increased in group F postoperatively. Whereas in group T, IL-2 was unchanged 1 h after operation but was significantly elevated 3 and 24 h after operation. Our results showed that the inhibition of morphine on IL-2 was most probably related to its suppression on NF-κB, Fentanyl had different effects on human immune response in vitro and in vivo. Tramadol may have immune enhancing effect.

Multicenter Clinical Study for Evaluation of Efficacy and Safety of Transdermal Fentanyl Matrix Patch in Treatment of Moderate to Severe Cancer Pain in 474 Chinese Cancer Patients

Objective: Although a new matrix formulation fentanyl has been used throughout the world for cancer pain management, few data about its efficacy and clinical outcomes associated with its use in Chinese patients have been obtained. This study aimed to assess the efficacy and safety of the new system in Chinese patients with moderate to severe cancer pain. Methods: A total of 474 patients with moderate to severe cancer pain were enrolled in this study and were treated with the new transdermal fentanyl matrix patch (TDF) up to 2 weeks. All the patients were asked to record pain intensity, side effects, quality of life (QOL), adherence and global satisfaction. The initial dose of fentanyl was 25 ?g/h titrated with opioid or according to National Comprehensive Cancer Network (NCCN) guidelines. Transdermal fentanyl was changed every three days. Results: After 2 weeks. The mean pain intensity of the 459 evaluated patients decreased significantly from 5.63?1.26 to 2.03?1.46 (P<0.0001). The total remission rate was 91.29%, of which moderate remission rate 53.16%, obvious remission rate 25.49% and complete remission rate 12.64%. The rate of adverse events was 33.75%, 18.78% of which were moderate and 3.80% were severe. The most frequent adverse events were constipation and nausea. No fatal events were observed. The quality of life was remarkably improved after the treatment (P<0.0001). Conclusion: The new TDF is effective and safe in treating patients with moderate to severe cancer pain, and can significantly improve the quality of life.

Determination of structure-activity relationships between fentanyl analogs and human μ-opioid receptors based on active binding site models

Fentanyl is a potent and widely used clinical narcotic analgesic, as well as a highly selective IJ-opioid agonist. The present study established a homologous model of the human μ-opioid receptor; an intercomparison of three types of μ-opioid receptor protein sequence homologous rates was made. The secondary receptor structure was predicted, the model reliability was assessed and verified using the Ramachandran plot and ProTab analysis. The predictive ability of the CoMFA model was further validated using an external test set. Using the Surflex-Dock program, a series of fentanyl analog molecules were docked to the receptor, the calculation results from Biopolymer/SitelD showed that the receptor had a deep binding area situated in the extracellular side of the transmembrane domains （TM） among TM3, TM5, TM6, and TMT. Results suggested that there might be 5 active areas in the receptor. The important residues were Asp147, Tyr148, and Tyr149 in TM3, Trp293, and His297 in TM6, and Trp318, His319, Ile322, and Tyr326 in TM7, which were located at the 5 active areas. The best fentanyl docking orientation position was the piperidine ring, which was nearly perpendicular to the membrane surface in the 7 TM domains. Molecular dynamic simulations were applied to evaluate potential relationships between ligand conformation and fentanyl substitution.

Identification of factors associated with sedation tolerance in 5000 patients undergoing outpatient colonoscopy:Canadian tertiary center experience

AIM To develop a prediction model aimed at identifying patients that may require higher than usual sedation doses during colonoscopy.METHODS A retrospective chart review on 5000 patients who underwent an outpatient colonoscopy at St.Paul's Hospital from 2009 to 2010 was conducted in order to develop a model for identifying patients who will require increased doses of sedatives.Potential predictor variables including age,gender,endoscopy indication,high sedation requirements during previous endoscopies,difficulty of the procedure,bowel preparation quality,interventions,findings as well as current use of benzodiazepines,opioids and alcohol were analyzed.The outcome of study was the use ofhigh dose of sedation agents for the procedure.In particular,the high dose of sedation was defined as fentanyl greater than 50 mcg and midazolam greater than 3 mg.RESULTS Analysis of 5282 patients(mean age 57 ± 12,49% female) was performed.Most common indication for the procedure was screening colonoscopy(57%).Almost half of our patients received doses exceeding Fentanyl 50 mcg and Midazolam 3 mg.Logistic regression models identified the following variables associated with high sedation:Younger age(OR=0.95 95%CI:0.94-0.95;P < 0.0001);abdominal pain(OR=1.45,95%CI:1.08-1.96);P=0.01) and Inflammatory Bowel Disease(OR=1.45,95%CI:1.04-2.03;P=0.02) as indications for the procedure;difficult procedure as defined by gastroenterologist(OR=1.73,95%CI:1.48-2.03;P < 0.0001);past history of abdominal surgery(OR=1.33,95%CI:1.17-1.52;P <0.0001) and previous colonoscopy(OR=1.39,95%CI:1.21-1.60;P=0.0001) and alcohol use(OR=1.26,95%CI:1.03-1.54;P=0.02).Age and gender adjusted analysis yielded inflammatory bowel disease as an indication(OR=3.17,95%CI:1.58-6.37;P=0.002);difficult procedure as defined by an endoscopist(OR=5.13 95%CI:2.97-8.85;P=0.0001) and current use of opioids,benzodiazepines or antidepressants(OR=2.88,95%CI:1.74-4.77;P=0.001) having the highest predictive value of high sedation requirements.Our prediction model using the following pre-procedural variables including age,indication for the procedure,medication/substance use,previous surgeries yielded an area under the curve of 0.76 for Fentanyl ≥ 100 mcg and Midazolam ≥ 3 mg.CONCLUSION Pre-procedural planning is the key in conducting successful,efficient colonoscopy.Logistic regression analysis of 5000 patients who underwent out-patient colonoscopy revealed the following factors associated with increased sedation requirement:Younger age,female gender,difficult endoscopy,specific indications as well as cardiopulmonary complications and current use of opioids/benzodiazepines.Age and gender adjusted analysis yielded similar results.These patients are more likely to need a longer recovery periods post-endoscopy,which could result in additional time and personnel requirements.The final predictive model has good predictive ability for Fentanyl ≥ 100 mcg and Midazolam ≥ 3 mg and fair predictive ability for Fentanyl ≥ 50 mcg and Midazolam ≥ 2 mg.The external validity of this model is planned to be tested in another center.

Efficiency and patient experience with propofol vsconventional sedation:A prospective study

AIM: To determine whether anaesthesiologistadministered sedation with propofol(AAP) or endoscopist-administered conscious sedation(EAC) with fentanyl/midazolam shortens colonoscopy duration/total room time. METHODS: This is a prospective, non-randomized, comparative study that enrolled patients greater than 18 years of age undergoing colonoscopy in a single Canadian academic outpatient endoscopy unit over a three-month consecutive period. Colonoscopies in this unit are performed both with AAP and EAC. Patient demographics, procedure-related data and adverse events were documented. Additionally, the level of procedure difficulty, and whether a staff endoscopist, trainee with assistance, or independent trainee, performed the procedure were documented. A validated modified 4-question, 5-point Likert scale telephone survey was used to assess patient satisfaction with colonoscopy. The telephone patient satisfaction survey was conducted 24-72 h following the procedure.RESULTS: Two hundred and thirty patients were enrolled during the study period with 126 patients in the AAP group and 104 patients in the EAC group. Mean procedure time was 18.3 ± 10.1 min in the AAP group and 14.7 ± 7.1 min in the EAC group(P = 0.002). Mean total room time was 36.8 ± 13.7 with AAP and 30.1 ± 11 min with EAC(P < 0.001). Multivariate analysis revealed the use of AAP(P = 0.002), resident participation(P < 0.001), diagnostic interventions(P = 0.033), therapeutic interventions(P < 0.001), lower body mass index(P = 0.008) and American Society of Anaesthesiologist class(P = 0.016), to be predictors of longer total room time. Patient age and gender were not significant predictors. After excluding cases in which trainees were involved, there was no significant difference in procedure time between the two groups(P = 0.941), however total room time was still prolonged in the AAP group(P = 0.019). The amount of pain experienced was lower with AAP(P = 0.02), with a trend toward overall higher patient satisfaction(P = 0.074). There were 2 sedation-related adverse events, both in the AAP group involving a patient with aspiration requiring hospitalization and a patient with hypoxia managed with bronchodilators.CONCLUSION: EAC results in reduced total room time compared to AAP. Resident participation doubles procedure time regardless of sedation type.

罗哌卡因联合舒芬太尼用于全膝关节置换术后硬膜外镇痛效果观察

目的:探讨舒芬太尼联合罗哌卡因在全膝关节置换(TKA)术后患者自控硬膜外镇痛的效果观察。方法:选择80例ASAI^II级全膝关节置换术后患者,随机分为4组,L组、S1组、S2组、S3组,实施患者自控硬膜外镇痛(PCEA),L组为0.1%罗哌卡因50 ml,S1组为0.1%罗哌卡因50 ml(含舒芬太尼0.25μg/ml),S2组为0.1%罗哌卡因50 ml(含舒芬太尼0.5μg/ml),S3组为0.1%罗哌卡因50 ml(含舒芬太尼0.75μg/ml),观察并记录术后1 h、6 h、12 h、24 h休息与被动运动的视觉模拟评分(VAS),同时记录低血压、恶心/呕吐、瘙痒等不良反应。结果:术后休息与被动运动的疼痛评分(VAS)均<2.5。术后瘙痒的发生率S1组明显低于S2组、S3组。结论:S1组(0.1%罗哌卡因+舒芬太尼0.25μg/ml)术后瘙痒的发生率明显降低。因此,TKA术后PCEA镇痛的最适剂量为舒芬太尼0.25μg/ml。

Conversing Rate from Morphine to Continuous Infusion of Fentanyl in Patients Suffering Cancer Pain

Objective： To investigate the proper conversing rate from morphine to continuous infusion of fentanyl in patients suffering cancer pain. Methods： A retrospective study was carried on in 20 patients with cancer pain in Shizuoka Cancer Center from Sep. 2002 to Nov. 2003. Pain intensity, adverse reactions, and satisfaction index of patients were evaluated. Results： The pain intensity was stable in 17 patients indicating good pain-control within 1 week after conversion and unstable in 3 patients after conversion suggesting poor pain-control. Fentanyl injection could alleviate side effects and increase the satisfaction index of patients. Conclusion： The equipotent ratio for conversion of low dose morphine to fentanyl injection was established as 72：1, and for non low dose morphine a ratio less than 72：1 was proposed to get stable pain-relieving effect. But the equipotent ratio for conversion of morphine to continuous infusion of fentanyl could not be determined. We must consider the morphine dose before the confirmation of the conversing rate.

Comparison between intravenous morphine versus fentanyl in acute pain relief in drug abusers with acute limb traumatic injury

BACKGROUND: Rapid and effective pain relief in acute traumatic limb injuries(ATLI) is one of the most important roles of emergency physicians. In these situations, opioid addiction is an important concern because of the dependency on opioids. The study aims to compare the effectiveness of intravenous(IV) fentanyl versus morphine in reducing pain in patients with opioid addiction who suffered from ATLI.METHODS: In this double-blind randomized clinical trial, 320 patients with ATLI, who presented to the emergency department(ED) from February 2016 to April 2016, were randomly divided into two groups. One group(160 patients) received 0.1 mg/kg IV morphine. The other group(160 patients) received 1 mcg/kg IV fentanyl. Patients' demographic data, pain score at specif ic intervals, vital signs, side effects, satisfaction and the need for rescue analgesia were recorded.RESULTS: Eight patients in the morphine group and five patients in the fentanyl group were excluded. Pain score in the fentanyl group had a significant decrease at 5-minute follow-up(P value=0.00). However, at 10, 30, and 60-minute follow-ups no signifi cant differences were observed between the two groups in terms of pain score reduction. The rescue analgesia was required in 12(7.7%) patients in the fentanyl group and in 48(31.6%) patients in the morphine group(P value=0.00). No signifi cant difference was observed regarding side effects, vital signs and patients' satisfaction between the two groups.CONCLUSION: Fentanyl might be an effective and safe drug in opioid addicts suffering from ATLI.