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.

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.

Neonatal Cord Tox Panel and Maternal Perinatal Fentanyl Exposure: A Retrospective Chart Review

Objective: The specific aim of this study was to determine if the currently available cutoff for fentanyl in umbilical cord (UC) was appropriate to distinguish illicit fentanyl exposure from therapeutic in-hospital administration of fentanyl. Study Design: Medical record review was conducted for perinatal administration of fentanyl and the detection of fentanyl in the corresponding routine UC toxicology. Specimens were initially tested with immunoassay followed by mass spectrometry (n = 62). Result: Excluding a single specimen that was confirmed positive, specimens were below the assays’ limit of quantification. The immunoassay’s mean b/b0 for the cases that received and did not receive fentanyl prior to delivery was 91.3% ± 10.6% and 98.2% ± 6.5%, respectively (p = 0.003). Conclusion: We demonstrated that UC is a suitable specimen type for the detection of fentanyl and that the cutoff selected adequately identifies illicit fentanyl use while not flagging cases where fentanyl was administered by the hospital prior to birth.

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.

Using Umbilical Cord Tissue to Identify Prenatal Exposure to Fentanyl and Other Commonly Abused Drugs

Background: Prenatal exposure to fentanyl may lead to Neonatal Abstinence Syndrome (NAS), a constellation of symptoms observed when newborns begin withdrawing from addictive substances such as opioids. The use of umbilical cord tissue segments (UC) for newborn toxicology has been increasing due to its apparent long detection window, sensitivity, and ease of collection. However, very little has been reported in the literature concerning the prevalence of in utero exposure to fentanyl and co-exposure with other commonly abused substances. Specific aim: The specific aims of this retrospective study are twofold. We will report prevalence of neonatal exposure to fentanyl for a nationwide high-risk population using UC submitted to a national reference laboratory for routine forensic toxicology analysis and the co-exposure patterns observed for these fentanyl-exposed neonates. Methods: A secondary analysis was performed using historical data for UC received between January 1, 2020 and December 31, 2020 for routine forensic toxicology analysis. Results: During the study period, our laboratory received 23,104 UC for analysis and 9667 (41.8%) of those UC were positive for at least one drug. The prevalence of fentanyl detection was 1.9% (n = 429). Of these 429 specimens there were 407 UC where both fentanyl and norfentanyl were detected. There were 14 UC where only fentanyl was detected and 8 UC where only norfentanyl was detected. When detected, the median concentrations of fentanyl and norfentanyl were 4029 pg/g (IQR: 1696, 9230 pg/g) and 10,756 pg/mg (IQR: 3925, 25,288 pg/g), respectively. Of the 429 positive fentanyl and/or norfentanyl UC, 33 (7.7%) were only positive for fentanyl and/or norfentanyl. Of the 396 polypositive UC, morphine was the highest co-exposure with 243 UC (56.6%) being positive for both fentanyls and morphine. The second most prevalent co-exposure observed was methamphetamine/amphetamine (n = 173;40.3%) followed by cannabinoids (n = 113;26.3%) and benzoylecgonine (cocaine metabolite;n = 106;24.7%). Conclusions: Nonmedical use of fentanyl is an alarming trend in this country including this maternal demographic reported here. Fentanyl was typically found with other commonly abused substances.

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.

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.

Efficacy and Safety of Transdermal Fentanyl(TDF)in Treatment of Pain Caused by Interventional Embolization Therapy

Objective： Interventional embolization therapy is well accepted in cancer treatment, but patient may suffer from a moderate-to-severe pain after therapy and its quality of life （QoL） is influenced, this study is to observe the efficacy and safety of transdermal fentanyl （TDF） in the management of pain caused by interventional embolization therapy. Methods： Morphine 10mg and TDF 25μg/h were immediately used in 52 patients who had moderate-to-severe pain complicated by interventional embolization therapy, the pain intensity was evaluated by visual analogue scale （VAS）. If VAS≥4 at t2 h after treatment, the dosage of TDF added into 50 μg/h. At 0h, 12h, 24h, 72h, 1 week, 2 weeks after TD, the vas and adverse events were observed respectively. Result： There was an obvious decrease in VAS at 12h after TDF treatment in the patients of which only 9 patients used 50ug/h dosage after partial splenic embolization （PSE） therapy. Most patients got satisfactory pain relief both the TDF 25 μg/h and TDF 50 μg/h group （VAS 0-1）. The adverse events were nausea, vomiting and dizzy, especially in the TDF 50 μg/h group. No respiratory depression was observed and only one patient got retention of urine. Conclusion： TDF was effective and safe in the treatment of moderate-to-severe pain after interventional embolizafion therapy.

Three-dimensional pharmacophore screening for fentanyl derivatives

Fentanyl is a highly selective u-opioid receptor agonist with high analgesic activity. Three-dimensional pharmacophore models were built from a set of 50 fentanyl derivatives. These were employed to elucidate ligand-receptor interactions using information derived only from the ligand structure to identify new potential lead compounds. The present studies demonstrated that three hydrophobic regions, one positive ionizable region and two hydrogen bond acceptor region sites located on the molecule seem to be essential for analgesic activity. The results of the comparative molecular field analysis model suggested that both steric and electrostatic interactions play important roles. The contributions from steric and electrostatic fields for the model were 0.621 and 0.379, respectively. The pharmacophore model provides crucial information about how well the common features of a subject molecule overlap with the hypothesis model, which is very valuable for designing and optimizing new active structures.

Membrane Separator Interface for Mass-Spectrometric Analysis of Desflurane, Propofol and Fentanyl in Plasma and Cerebrospinal Fluid

Mass-spectrometric interface for the measurement of anaesthetic agent concentration in biological fluids (blood plasma and cerebrospinal fluid) is described. Sampling of biological fluids was performed during balanced inhalational (desflurane, fentanyl) anaesthesia and total intravenous (propofol, fentanyl) anaesthesia. The described method for drug concentration measurement in biologic fluids does not require long-term sample processing before injecting the sample into mass-spectrometer interface, in contrast to chromatographic methods. A hydrophobic membrane was used in the interface to separate anaesthetic agents from biological fluids: inhalational anaesthetic desflurane, hypnotic propofol, analgesic fentanyl. A possibility to use the interface for measurement of desflurane and propofol absolute concentration in blood plasma and cerebrospinal fluid was demonstrated for the study of blood-brain barrier (BBB) properties.

Effect of pretreatment with different concertrations of morphine, fentanyl and tramadol on the differentiation of human helper T cells in vitro

Objective： To investigate and compare the .effects of different concentrations of morphine, fentanyl and tramadol on the differentiation of human adult helper T cells in vitro. Methods： Twenty out-patients without immune disease were selected and their peripheral blood was collected. Then the Whole blood of peripheral blood mononuclear cells （PBMCs） were pretreated with different concentration of morphine, fentanyl and tramadol for 24 h. The level of CD4^＋ IFN-γ^＋ IL-2^＋/CD4^＋ IL-4^＋ IL-10^＋ was analyzed by three-color flow cytometry, and the CD4^＋ CCR5^＋ and CD4^＋ CCR3 ^＋ cells were counted to observe the imbalance of Th2/Th2. Results： The number of Th2 increased significantly and the ratio of Th2/Th2 decreased dramatically compared with the control group, and there was a dose-dependent fashion in all drugs. Conclusion： Morphine, fentanyl and tramadol can direct Th0 cells toward Th2 differentiation, especially morphine and fentanyl.

Effects of Dexamethasone, Clonidine, Tramadol and Nalbuphine on Fentanyl-Induced Hyperalgesia in Rats

Opioids are drugs used to alleviate pain. However, studies have demonstrated that these drugs can cause an increase in pain sensitivity, which is called opioid-induced hyperalgesia. The objective of this study was to describe the effects of dexamethasone, clonidine, tramadol and nalbuphine on fentanyl-induced hyperalgesia in rats. After obtaining approval from the Committee for the Ethical Use of Animals (CEUA), 36 male Wistar rats were divided into 6 groups: Group 1 (GCSSL) wherein the rats received 1 ml 0.9% saline solution in two injections;Group 2 (GFTSL), received fentanyl at a dose of 100 ug·kg-1 followed by 1 ml 0.9% saline solution via intraperitoneal;the remaining groups (3, 4, 5, 6) received fentanyl at a dose of 100 ug·kg-1 following doses via intraperitoneal: Group 3 (GFTDX), dexamethasone at a dose of 1.0 mg·kg-1;Group 4 (GFTCL), clonidine at a dose of 20 mg·kg-1;Group 5 (GFTTR), tramadol at a dose of 50 mg·kg-1, and Group 6 (GFTNB), nalbuphine at a dose of 5 mg·kg-1. Under general anestesia using isoflurane, the animals were submitted to a surgical incision. Hyperalgesia was evaluated by applying Von Frey filaments at 2 hours after the incision and on the 1st, 3rd and 5th days afterward. At 2 hours after the surgical procedure, there was lower intensity of pain in the fentanyl group (GFTSL) compared to the other groups, and on the fifth day there were no significant differences for pain intensity between groups. The results suggest the presence of fentanyl-induced hyperalgesia and efficacy in its reduction by dexamethasone, clonidine, tramadol and nalbuphine.

ADSORPTIVE STRIPPING VOLTAMMETRY OF A FENTANYL DERIVATIVE DNPME AT Hg ELECTRODE

A quasi-reversible reduction peak of a fentanyl derivative DNPME is found by cyclic voltammetry at Hg electrode. E_(pc)=-1.58 V (vs. Ag/AgCl). The cathodic peak shows adsorptive characteristics. The adsorbed species is DNPME neutral molecule. The method for measuring trace amount of DNPME by adsorptive stripping voltammetry is established.

Effects of Ketoprofen, Ketamine, Lidocaine and Propofol on Fentanyl-Induced Hyperalgesia in Rats

Opioid-induced hyperalgesia negatively affects physiological pain management and presents a complex causal mechanism, involving, pharmacodynamic and pharmacokinetic factors of interactions with receptors, opioid-independent ascending systems and with pro-nociceptive systems. After approval by the CEUA, 42 male Wistar rats were divided into 7 groups: In group 1 (GCSSL) the animals received 1 ml of 0.9% saline solution intraperitoneally (IP);in group 2 (GFTSL), they received fentanyl at a dose of 100 ug·kg-1 IP;in the remaining groups (3, 4, 5, 6 and 7) the animals received IP, fentanyl at a dose of 100 ug·kg-1 followed also by IP route of: group 3 (GFTKP) ketoprofen at a dose of 5 mg·kg-1;group 4 GFTKT), ketamine up to a dose of 10.0 mg·kg-1;group 5 (GFTLI), incisional lidocaine up to a dose of 10 mg·kg-1;group 6 (GFTLP), intraperitoneal lidocaine up to a dose of 10 mg·kg-1 and group 7 (GFTPP), propofol up to a dose of 60 mg·kg-1. Under general anesthesia, all animals with a plantar surgical incision. Hyperalgesia was evaluated by applying Von Frey filaments on the 2nd, 1st, 3rd and 5th days after treatment. In the 2nd hour and on the 5th day after the procedure, there was no hyperalgesia associated with the use of fentanyl, however, on the 1st and 3rd postoperative days there was hyperalgesia that was attenuated by ketoprofen, ketamine, lidocaine infiltrated in the incision and intraperitoneally, an effect not observed with the use of propofol. The results suggest fentanyl-induced hyperalgesia and the efficacy of ketoprofen, ketamine, incisional lidocaine and intraperitoneal lidocaine in reducing this effect.

Effects on newborns of applying bupivacaine combined with different doses of fentanyl for cesarean section

BACKGROUND The choice of anesthesia for cesarean section is very important.AIM To compare the effects of applying bupivacaine combined with different doses of fentanyl on newborns after cesarean section.METHODS We randomly divided one hundred and twenty patients undergoing cesarean section into the following 4 groups:group B(bupivacaine group),group BF10(bupivacaine combined with 10μg fentanyl),group BF30(bupivacaine combined with 30μg fentanyl)and group BF50(bupivacaine combined with 50μg fentanyl).The heart rate,mean arterial pressure,block plane fixation time and sensory block time were recorded.Umbilical artery blood was then collected immediately after fetal delivery for blood gas analysis and qualitative detection of fentanyl.Additionally,data on the neonatal 1-min and 5-min Apgar scores,results of umbilical artery blood gas analysis and qualitative detection of fentanyl in umbilical artery blood were recorded.RESULTS Although the mean arterial pressure decreased in all four groups at 3 min after anesthesia,the percentage of the decrease was less than 20%of the baseline.In addition,there were no significant differences in the 1-min or 5-min Apgar scores or the umbilical artery blood gas analysis among the four groups(P>0.05).Moreover,the concentration of fentanyl in umbilical artery blood was qualitatively detected using an ELISA kit,and the results in the four groups were negative.CONCLUSION Bupivacaine combined with fentanyl spinal anesthesia is effective in cesarean section.

Comparison of impact of adjuvant treatment of midazolam, fentanyl, and magnesium sulfate with intrathecal bupivacaine on block characteristics and postoperative analgesia in knee arthroplasty: A randomized clinical trial

Objective:To compare the efficacy of midazolam,fentanyl,and magnesium sulfate as adjuvants to intrathecal bupivacaine on both block characteristics and postoperative analgesia in knee arthroplasty.Methods:This randomized double-blind clinical trial recruited spinal anesthesia patients of the American Society of Anesthesiologists classⅠorⅡ,who needed knee arthroplasty.Patients were stratified into three intervention groups,including the midazolam group,the fentanyl group,and the magnesium sulfate group,and the patients were administered with midazolam,fentanyl,and magnesium sulfate,respectively.Hemodynamic parameters,sensory and motor block,and pain score(Visual Analogue Scale)were measured and compared among the three groups.Results:A total of 105 patients were included in this study with 35 patients in each group.There was no statistically significant difference in terms of oxygen saturation,mean blood pressure,duration of surgery,and postoperative complications,including nausea,vomiting,bradycardia,dizziness,and hypotension,as well as the time of opioid administration among the three groups(P>0.05).Statistically significant differences were found in terms of heart rate at 15,30,45,60,75,and 105 min after beginning of operation among the three groups,which was lower in the midazolam group(P<0.05).The midazolam group showed a shorter time to achieve sensory block after spinal anesthesia,sensory block to T8 or higher and sensory block to T12 and L1(P<0.05).Besides,the three groups showed significantly differences in terms of onset of motor block after spinal anesthesia and time to achieve motor block to T8 or higher or Bromage score 3(P=0.001).No significant difference was noted in pain scores among the three groups(P>0.05).Conclusion:Midazolam resulted in a shorter time to achieve sensory and motor block to T8 or higher,the onset of motor block and sensory block after spinal anesthesia,and time to achieve sensory block to T12 and L1,and the pain scores were not significantly different among the groups.Thus,midazolam can be highly underlined,if a shorter onset of sensory and motor blocks is targeted.[Funded by the research deputy of Arak University of Medical Sciences(No.99258);fa.irct.ir number,IRCT20141209020258N164].

No relationship between the incidence of fentanyl-induced cough and smoking

The purpose of the study was to investigate whether or not the incidence of cough after intra-venous fentanyl depends on the patient’s smoking state and the speed of injection. 530 ASA class I-III patients free of bronchial hyperreactivity and res-piratory tract infection undergoing general anes-thesia for elective surgery were randomized to 1.5 g.kg-1 fentanyl injected over 2, 5 or 10 sec or pla-cebo via a peripheral intravenous cannula. The endpoint was cough within 5 min after completion of injection. Statistical evaluation was performed by factorial ANOVA and chi-square-test. Assuming around 25% smokers in our patient population calculated patient sample size was 340 per group. The study was terminated for futility after enrol-ment of 530 patients since an interims analysis yielded an incidence of cough of 2 % both in smokers (n=174) and nonsmokers (n=356, p= 0,970), which was unrelated to the speed of injec-tion and not different from placebo.

Inhibitory Effect of Fentanyl on Phenylephrine-Induced Contraction on Rabbit Aorta

This in vitro study was designed to assess the effects of fentanyl on isolated rabbit thoracic aorta rings contracted with phenylephrine. Methods included contraction of aorta rings with phenylephrine (10–5 M) and recording the changes after increasing concentrations of fentanyl (10–9 M – 10–5 M). Similar experiments were done after incubation with Nω- nitro-L-arginine methyl ester (10–4 M), indomethacin (10-5 M), naloxone (10–5 M), ouabain (10–5 M), TEA (10–4 M) and glibenclamide (10–5 M). It was revealed that, fentanyl causes relaxation in rabbit aorta rings precontracted with phenylephrine. Removal of endothelium significantly reduces the relaxant response to fentanyl. Nitric oxide synthase inhibitor L-NAME, K+ channel blocker glibenclamide and Na+/K+ ATPase inhibitor ouabain inhibits the relaxant effect of fentanyl in endothelium intact aorta rings. These results suggest that fentanyl causes dose dependent vasodilatation in the rabbit aorta via activation of KATP channels and Na+-K+ -ATPase, and nitric oxide released from endothelium.