Fentanyl versus Dexmedetomidine Infusion in Head and Neck Free Flap Surgery for Comparison of Hemodynamic Parameters and Anaesthetic Requirements: A Randomised Controlled Trial.

BACKGROUND: This prospective, double-blinded, randomized study aimed to compare the efficacy of dexmedetomidine and fentanyl infusions in maintaining hemodynamics during head and neck free flap surgery, as well as their impact on the relative amount of blood loss. METHODS: Twenty patients with American Society of Anesthesiologists physical status I and II scheduled for elective head and neck free flap surgery were enrolled. The patients were randomly assigned to receive either dexmedetomidine (1 µg/kg over 10 min at anesthesia induction, followed by 0.2 to 0.75 µg/kg per hour infusion during maintenance) or fentanyl (1 to 2 µg/kg per hour infusion during maintenance). Intraoperative hemodynamic parameters, blood loss, blood transfusion requirements, surgeon satisfaction, adverse drug effects, and free flap survival up to 7 days were recorded. RESULTS: The dexmedetomidine group achieved a mean arterial pressure (MAP) value between 60 and 70 mmHg at multiple time points (15 min, 3rd, 4th, 5th, and 6th hours), while the fentanyl group did not reach this range at any time point. The intergroup statistical analysis revealed a significant difference only at the 5th hour with (95% CI: -16.17 to -0.62) and P = 0.036. Additionally, the dexmedetomidine group exhibited lower heart rates (< 70/min) at several time points (15 min, 2nd, 3rd, 4th, 5th, and 6th hours) compared to the fentanyl group. The intergroup comparison indicated a statistically significant difference only at the 3rd hour with (95% CI: -20.94 to -0.45) and P = 0.042. CONCLUSION: Dexmedetomidine can be a useful adjuvant of GA for inducing controlled hypotension and decreasing bleeding in free flap surgery of the head and neck region without any detrimental effect on the free flap survival.

Fentanyl: New Wave, New Age, New Addiction?

This paper aims to take over the rampant phenomenon of the illicit use/abuse for volutary purposes of fentanyl. This synthetic drug is normally used as a potent anaesthetic and analgesic molecule. Unfortunately, in recent decades, this substance has conquered and seduced millions of people in the 'westernised' world, claiming numerous victims, especially young people. To this end, the most recent scientific literature will be examined and the pharmacological effects of both therapeutic and intentional abuse will be considered. Finally, the consequences and psychosocial damage produced will be described.

Recognizing serotonin syndrome in the intensive care unit: a case report of serotonin syndrome in a patient taking amitriptyline, buprenorphine, pregabalin, and fentanyl.

Background: Despite its life-threatening nature, serotonin syndrome (SS) often eludes initial recognition and remains an underreported condition that can occur with the administration of serotonergic drugs alone or in combination with other medications known to increase levels of serotonin. The diagnosis of SS relies on clinical assessment, as laboratory tests and imaging studies cannot definitively confirm the condition. The majority of reported cases of SS involve polypharmacy rather than single-drug overdose. Diagnosing SS can be challenging for physicians, particularly in the intensive care unit (ICU) settings where patients often present with multiple comorbidities. Nevertheless, SS should be considered in the differential diagnosis, mainly when the treatment regimen includes multiple serotonergic medications. Case Description: We present a case of SS that developed in a patient following the administration of fentanyl. The patient had a medical history of opioid use disorder and was on buprenorphine, amitriptyline, and pregabalin. Symptoms indicative of SS appeared within four hours after fentanyl was administered and began to improve within six hours after cessation of the potential offending agents, with complete resolution occurring within 24 hours. Conclusions: Our case underscores the significance of conducting a thorough neurological examination and medication assessment for the prompt diagnosis of SS. Additionally, it examines the medications that could have potentially triggered the events described in this case.

Comparative Analysis of Intrathecal Bupivacaine With Fentanyl Versus Intrathecal Bupivacaine With Midazolam in Lower Abdominal and Lower Limb Surgeries.

Many different adjuvants are added intrathecally along with local anaesthetics to prolong intraoperative and postoperative analgesia. Hence, this study aimed to compare intrathecal bupivacaine with fentanyl and bupivacaine with midazolam in lower abdominal and lower limb surgeries. Following permission from the Hospital Ethical Committee (Research Protocol No.: IESC/PGS/2022/143), the study was conducted on a sample of 60 patients, divided into two groups, Group F and Group M, with 30 patients each, representing the American Society of Anaesthesiologist's (ASA) grades I and II. The patients were between the ages of 18 and 60 and featured both males and females, scheduled to undergo elective surgical procedures on the lower abdomen and lower limbs via spinal anaesthesia. Group "F": 3 ml of 0.5% hyperbaric bupivacaine hydrochloride with 0.5 ml (25 mcg) of fentanyl (preservative-free) intrathecally. Group "M": 3 ml of 0.5% hyperbaric bupivacaine hydrochloride with 0.5 ml (2.5 mg) of midazolam (preservative-free) intrathecally. The primary aim was to study the onset of motor and sensory block and duration of analgesia with the addition of midazolam or fentanyl to 0.5% heavy bupivacaine in the sub-arachnoid block. A secondary aim was to evaluate the quality of anaesthesia and postoperative analgesia, determine the haemodynamic stability in the intraoperative and postoperative period in the two study groups, and observe any adverse effects of study drugs. Group F exhibited a substantially longer duration for both sensory (211.5 vs. 154.4 min) and motor blockade (269.8 vs. 214.6 min) compared to Group M, as well as a rapid onset time for both sensory (2.6 vs. 3.3 min) and motor blockade (3.1 vs. 3.9 min). Also, Group F had a significantly longer duration of effective analgesia compared to Group M (266 ± 15.9 vs. 197.6 ± 13.7 minutes). The addition of 0.5 ml (2.5 mg) Midazolam with 0.5% hyperbaric Bupivacaine intrathecally prolonged the duration of anaesthesia and postoperative analgesia; however, fentanyl 0.5 ml (25 mcg) has a more prolonged duration of intraoperative and postoperative analgesia.

In vitro and in vivo study of butyrylfentanyl and 4-fluorobutyrylfentanyl in female and male mice: Role of the CRF1 receptor in cardiorespiratory impairment.

BACKGROUND AND PURPOSE: Fentanyl analogues have been implicated in many cases of intoxication and death with overdose worldwide. The aim of this study is to investigate the pharmaco-toxicology of two fentanyl analogues: butyrylfentanyl (BUF) and 4-fluorobutyrylfentanyl (4F-BUF). EXPERIMENTAL APPROACH: In vitro, we measured agonist opioid receptor efficacy, potency, and selectivity and ability to promote interaction of the µ receptor with G protein and ß-arrestin 2. In vivo, we evaluated thermal antinociception, stimulated motor activity and cardiorespiratory changes in female and male CD-1 mice injected with BUF or 4F-BUF (0.1-6 mg·kg-1). Opioid receptor specificity was investigated using naloxone (6 mg·kg-1). We investigated the possible role of stress in increasing cardiorespiratory toxicity using the corticotropin-releasing factor 1 (CRF1) antagonist antalarmin (10 mg·kg-1). KEY RESULTS: Agonists displayed the following rank of potency at µ receptors: fentanyl > 4F-BUF > BUF. Fentanyl and BUF behaved as partial agonists for the ß-arrestin 2 pathway, whereas 4F-BUF did not promote ß-arrestin 2 recruitment. In vivo, we revealed sex differences in motor and cardiorespiratory impairments but not antinociception induced by BUF and 4F-BUF. Antalarmin alone was effective in blocking respiratory impairment induced by BUF in both sexes but not 4F-BUF. The combination of naloxone and antalarmin significantly enhanced naloxone reversal of the cardiorespiratory impairments induced by BUF and 4F-BUF in mice. CONCLUSION AND IMPLICATIONS: In this study, we have uncovered a novel mechanism by which synthetic opioids induce respiratory depression, shedding new light on the role of CRF1 receptors in cardiorespiratory impairments by µ agonists.

Fentanyl enhances immune cell response through TLR4/MD-2 complex.

Introduction: Opioids have been shown to induce neuroinflammation and immune cell activation, that might contribute to some of the opioid side effects, such as opioid-induced tolerance and paradoxical hyperalgesia. In this context, TLR4/MD-2 complex has been proposed as an off-target site for opioid action. This study was aimed at investigating the effect of fentanyl on lipopolysaccharide (LPS)-induced TLR4/MD-2 activation in rat primary microglia and human monocyte-derived macrophages (MDM). Materials and Methods: The effect of fentanyl was first explored by measuring the expression and release of different proinflammatory mediators in primary rat microglia and human MDM by real-time PCR and ELISA. Then, the involvement of TLR4/MD-2 signaling was investigated studying NF-κB activation in HEK293 cells stably transfected with human TLR4, MD-2, and CD14 genes (HEK-Blue hTLR4 cells) and in human MDM. Results: Fentanyl increased mRNA levels, as well as the LPS-induced secretion of proinflammatory mediators in primary microglia and MDM. Two inhibitors of TLR4/MD-2 signaling, namely the oxazoline derivative of N-palmitoylethanolamine (PEA-OXA) and CLI-095, blocked the production and release of proinflammatory cytokines by microglia stimulated with LPS and fentanyl, suggesting that TLR4/MD-2 could be the target of the proinflammatory activity of fentanyl. Finally, we showed that fentanyl in combination with LPS activated NF-κB signaling in human MDM and in HEK-Blue hTLR4 cells and this effect was blocked by inhibitors of TLR4/MD-2 complex. Discussion: These results provide new insight into the mechanism of the proinflammatory activity of fentanyl, which involves the activation of TLR4/MD-2 signaling. Our findings might facilitate the development of novel inhibitors of TLR4/MD-2 signaling to combine with opioid-based analgesics for effective and safe pain management.

Illicitly Manufactured Fentanyl: Anesthesia's Role in the Perioperative Setting.

In wave 4 of the opioid crisis, which is dominated by illicitly manufactured fentanyl (IMF) and stimulant use, anesthesia personnel could play an important role in the perioperative care of these persons. Knowledge of the extent and lethality of opioid use in the current wave of the opioid crisis could raise awareness of the problem among anesthesia personnel. In the absence of research to guide development of best practice recommendations, knowledge of the historical trends in opioid use, the epidemiology of IMF use, and pragmatic clinically-oriented approaches for identifying persons using IMF could provide a general framework for future research.

A Fentanyl Hapten-Displaying Lipid Nanoparticle Vaccine that Non-Covalently Encapsulates a TLR7/8 Agonist and T-helper Epitope Induces Protective Anti-Fentanyl Immunity.

Opioid use disorder - particularly involving fentanyl - has precipitated a public health crisis characterized by a significant increase in addiction and overdose-related deaths. Fentanyl-specific immunotherapy, which aims at inducing fentanyl-specific antibodies capable of binding fentanyl molecules in the bloodstream, preventing their entry in the central nervous system, is therefore gaining momentum. Conventional opioid designs rely on the covalent conjugation of fentanyl analogues to immunogenic carrier proteins that hold the inherent capacity of mounting immunodominant responses. Here, we present an alternative fentanyl vaccine design that utilizes a non-covalent assembly of lipid nanoparticles (LNPs) to deliver fentanyl haptens in conjunction with a CD4+ T-helper peptide epitope and an imidazoquinoline TLR7/8 agonist. Our results demonstrate that a single intramuscular administration of the LNP-based nanovaccine elicits fentanyl-specific antibodies, significantly mitigating the effects of opioid overdose in preclinical mouse models. Furthermore, we analyzed the immunobiological behavior of the vaccine in vivo in mouse models, providing evidence that covalent attachment of a fentanyl hapten to a carrier proteins or peptide epitope is not necessary for inducing an effective immune response. However, co-delivery - specifically, the physical assembly of all immune cues into an LNP - remains essential for inducing hapten-specific immunity.

The effect of fentanyl on immobility after noxious stimulation in isoflurane-anaesthetized pigs: Exploring the role of the serotonergic system.

OBJECTIVE: To investigate if fentanyl induces immobility through activation of the serotonergic 5HT1A receptor, by using the 5HT1A-antagonist robalzotan. STUDY DESIGN: A prospective, blinded, randomized, two-group study. ANIMALS: A group of 12 mixed-breed pigs aged 71-79 days. METHODS: The motor response to clamping a claw was assessed in isoflurane-anaesthetized pigs at baseline, then fentanyl was infused intravenously (IV) for 40 minutes and clamping was repeated. The infusion started at 20 µg kg-1 hour-1 and was increased by 60% until fentanyl produced immobility, defined as no motor response for 60 seconds. Subsequently, either robalzotan (1 mg kg-1) or the same volume of saline was injected IV and clamping was repeated. The change in response was compared with Fisher's exact test. Mean arterial blood pressure (MAP) and heart rate (HR) were extracted for 2 minutes before and after 60 seconds of clamping, and the differences compared with a Wilcoxon signed-rank test. Dynamic respiratory compliance was calculated at baseline and after fentanyl; p < 0.05. RESULTS: Baseline clamping produced a motor response within 5 seconds. This was abolished by fentanyl. Robalzotan or saline did not alter this (p = 0.45). As a response to clamping, MAP and HR changed with median (range) -0.5 (-4.4 to 22.2) mmHg and -1 (-7 to 1.5), respectively, where HR changed significantly (p = 0.039). The 95% confidence interval for the effect size of fentanyl upon dynamic compliance was -3.25 to -1.65 mL cmH2O-1. CONCLUSIONS AND CLINICAL RELEVANCE: No indication was found for the 5HT1A receptor to be involved in fentanyl-induced reduction of the motor response to claw clamping. The decreased compliance after fentanyl could suggest onset of chest wall rigidity.

A Review of Toxicological Profile of Fentanyl-A 2024 Update.

Fentanyl and its analogues are synthetic opioids of varying potencies that are unfortunately heavily abused. Over the last 15 years, fentanyl and its analogues have contributed to the increasing prominence of hospitalisation and numerous deaths due to drug overdose. In this comprehensive literature review, the mechanism of toxicity of the drug in humans is evaluated. A systematic approach was used whereby the relevant literature has been detailed where the toxicity of fentanyl and/or its analogues to different organs/systems were investigated. Furthermore, the review covers the post-mortem toxicological data and demographic information from past fatal cases where fentanyl was believed to be involved. Such insight into fentanyl toxicity is useful as an aid to better understand the toxic doses of the drug and the suspected mechanism of action and the unexpected complications associated with overdose incidences involving the drug. Finally, the review offers an overview of the traditional and emerging test systems used to investigate the adverse effects of fentanyl on human health.

Xylazine abuse, the growing risk: A review of its effects, upsurge use and associated fatalities in the USA and Puerto Rico.

In the last decade, the opioid overdose epidemic has been exacerbated by the emerging drug of abuse, xylazine. This veterinary anesthetic, an alpha-2 agonist, not only potentiates the fatal effects of opioids but also causes toxic endothelial effects. This review aims to assess the impact of xylazine use and overdoses within the context of the opioid crisis as a public health issue. The research used data from scientific publications, state health reports, and analyses from the Institute of Forensic Sciences of Puerto Rico. The databases PubMed, Google Scholar, and Scopus were searched for relevant publications. The search strategy employed two groups of terms: the drug of interest (xylazine) and types of exposure (drug use, overdose, substance abuse, etc.). The initial search in PubMed was then extrapolated, and the search terms were adjusted for appropriate database syntax. According to the most recent publications and CDC data in the USA, approximately 95 % of fentanyl overdose cases involve xylazine, while the other 5 % of overdose cases are attributed solely to xylazine, predominantly administered intravenously. In the last four years, more than 4000 overdose deaths have been related to xylazine use; the northeastern United States had reported the most significant number of deaths. This number changes daily as reanalysis results and new data are published. Less than 50 % of states perform tests for xylazine detection or maintain statistical monitoring of overdoses related to this drug. The absence of testing impedes emergency room physicians from making accurate diagnoses, increasing the likelihood of fatal overdoses. This review highlights five major concerns: (1) The recognition of intoxication as a primary concern and the unavailability of alpha-2 antagonists for treatment. (2) The challenges in the clinical setting linked to xylazine abuse and its co-administration with substances like fentanyl and its analogs. (3) The necessity for robust government statistical resources for the unification and dissemination of critical overdose and emerging drug abuse detection information. (4) The need for effective rehabilitation programs, including psychosocial support and treatment interventions, to respond to this public health crisis. (5) The urgency for further research to understand the prevalence, toxic effects of chronic or acute use, and the clinical implications in xylazine users, including the development of alpha-2 antagonists for treatment. We conclude that addressing these concerns is crucial to working with the xylazine abuse situation.

Psychosocial Impact of Suspected Xylazine-Associated Skin Wounds Among People Using Fentanyl, Philadelphia, 2022 to 2023.

BACKGROUND: The United States opioid crisis has been worsened by the emergence of fentanyl adulterated or associated with the veterinary sedative xylazine. Designated by the White House as an "emerging threat to the US" in 2023, xylazine use is associated with severe skin wounds. METHODS: This research explored beliefs, concerns, and treatment behaviors for skin wounds among 93 participants recruited outside of a Philadelphia, Pennsylvania harm reduction agency who reported past-6-month history of a skin wound via a cross-sectional survey administered August-September 2022 (group 1; n = 33). Following a December 2022 Philadelphia Department of Public Health Report that indicated xylazine was becoming more prevalent in the Philadelphian drug supply, additional data was collected with new participants from February-March 2023 (group 2; n = 60) using the same survey. Participants were ≥18 years old, reported past-year fentanyl use, and spoke English. Our 17-item tool measured skin wound-related beliefs, concerns, treatment behaviors, and treatment sources. An open-response item explored why participants self-treat skin wounds. RESULTS: Participants averaged 41 years old (SD = 9), slightly more than half were men (n = 54, 58%), 31% (n = 29) were non-White, and most (n = 66, 71%) were unhoused. Overall, 79% of participants self-treated skin wounds. Participants endorsed worry about limb loss (n = 77; 83%), wound shame (n = 76; 82%), and appearance changes (n = 80; 86%). Sixty participants (65%) reported waiting to see wound severity before seeking care. Forty-one participants (44%) delayed wound care because of withdrawal fears. CONCLUSIONS: People with probable xylazine-associated skin wounds have psychosocial concerns about and self-treat these wounds. Findings may be a harbinger of skin wound harm in other regions of the United States and internationally where xylazine is increasing.

Use of fentanyl test strips by people who inject drugs: Baseline findings from the South Atlantic Fentanyl Test Strip Study (SAFTSS).

BACKGROUND: Research published during the early fentanyl period exposed a growing concern of unwitting fentanyl exposure and a general willingness to use fentanyl test strips (FTS). A paucity of FTS studies over the last several years has restricted our ability to understand FTS use in the late fentanyl era. The South Atlantic FTS Study (SAFTSS) was established to investigate contemporaneous changes in FTS use and drug use behavior among a rural cohort of PWID. METHODS: Between June 2021 and March 2022, a total of 541 PWID completed an in-person survey. Baseline survey questions included demographics, socioeconomic characteristics, and drugs used. FTS questions covered lifetime use, past 6-months, and past 30-day use and included reasons for using FTS, levels of access, and confidence testing illicit opioids and stimulants. Multivariable analyses examined significant baseline correlates of lifetime and 30-day FTS use. RESULTS: Overall, more than half (58%; N=315) used FTS in their lifetime. Among lifetime FTS users, almost half (47%) used FTS in the past 6 months and 30% in the past 30 days, with an average of 13 months from last FTS use and the baseline survey. The most common reason for not using FTS was "not having them with me when I use drugs." Less frequent reasons were "I already know it's fentanyl" followed by "FTS take too much time to use." Among past 30-day FTS users, 74% used FTS on heroin, 55% on methamphetamine, and 33% on fentanyl. Consumer confidence using FTS was higher with illicit opioids (66%) but lower for methamphetamine (43%). In both the lifetime and past 30-day models, PWID with FTS use were more likely than non-users to have witnessed an overdose in the past six months (lifetime aOR = 2.85, p<.001; 30-day aOR=2.57, p<.01). Virtually no differences in drug use behaviors were found when comparing past 30-days FTS use to no FTS use. Women (aOR=1.68, p<.05) and non-white PWID (aOR=2.43, p<.05) were more likely than men and white PWID to have used FTS. CONCLUSIONS: Declines in FTS use are consistent with what syringe services programs have been signaling for years. Needs assessments to gauge interest in FTS before scaling up can help ensure funding better spent on naloxone and syringes is not allocated to idle FTS. Increased FTS among women and racial minorities presents opportunities for tailored interventions. Recognizing trauma associated with witnessing overdoses as a growing component of the opioid epidemic is a critical first step toward addressing the full spectrum of drug-related harm.

Temporal and spatial trends of fentanyl co-occurrence in the illicit drug supply in the United States: a serial cross-sectional analysis.

Background: Fentanyl and its analogs contribute substantially to drug overdose deaths in the United States. There is concern that people using drugs are being unknowingly exposed to fentanyl, increasing their risk of overdose death. This study examines temporal trends and spatial variations in the co-occurrence of fentanyl with other seized drugs. Methods: We identified fentanyl co-occurrence (the proportion of samples of non-fentanyl substances that also contain fentanyl) among 9 substances or substance classes of interest: methamphetamine, cannabis, cocaine, heroin, club drugs, hallucinogens, and prescription opioids, stimulants, and benzodiazepines. We used serial cross-sectional data on drug reports across 50 states and the District of Columbia from the National Forensic Laboratory Information System, the largest available database on the U.S. illicit drug supply, from January 2013 to December 2023. Findings: We analyzed data from 11,940,207 samples. Fentanyl co-occurrence with all examined substances increased monotonically over time (Mann-Kendall p < 0.0001). Nationally, fentanyl co-occurrence was highest among heroin samples (approx. 50%), but relatively low among methamphetamine (≤1%), cocaine (≤4%), and other drug samples. However, co-occurrence rates have grown to over 10% for cocaine and methamphetamine in several Northeast states in 2017-2023. Interpretation: Fentanyl co-occurs most commonly with heroin, but its presence in stimulant supplies is increasing in some areas, where it may pose a disproportionately high risk of overdose. Funding: This work was partly supported by FDA grant U01FD00745501. This article reflects the views of the authors and does not represent the views or policies of the FDA or US Department of Health and Human Services.

Sex disparities in outcome of medication-assisted therapy of opioid use disorder: Nationally representative study.

Question: The opioid epidemic causes massive morbidity, and males have substantially greater overdose mortality rates than females. It is unclear whether there are sex-related disparities at different stages in the trajectory of opioid use disorders, in "real world" settings. Goal: To determine sex disparities in non-medical opioid use (NMOU) at the end of outpatient medication-assisted treatment (MAT), using nationally representative data. Design: Observational epidemiological study of publicly funded outpatient MAT programs in the national "Treatment episode data set-discharges" (TEDS-D) for 2019. Participants: Persons aged ≥18 in their first treatment episode, in outpatient MAT for use of heroin or other opioids (N=11,549). The binary outcome was presence/absence of NMOU. Results: In univariate analyses, males had significantly higher odds of NMOU, compared to females (odds ratio=1.27; Chi2 [df:1]=39.08; uncorrected p<0.0001; p=0.0041 after Bonferroni correction). A multivariable logistic regression detected a male>female odds ratio of 1.19 (95%CI=1.09-1.29; p<0.0001), adjusting for socio-demographic/clinical variables. Several specific conditions were revealed in which males had greater odds of NMOU compared to females (e.g., at ages 18-29 and 30-39; corrected p=0.012, or if they used opioids by inhalation; corrected p=0.0041). Conclusions: This nationally representative study indicates that males have greater odds of NMOU in their first episode of MAT, indicating more unfavorable outcomes. The study reveals specific socio-demographic and clinical variables under which this sex disparity is most prominent.

Prescription opioid use in Israel - the tide has risen, but it's not a tidal wave.

The devastating human and financial costs of the ongoing global opioid crisis underscore the need for comprehensive public health strategies, effective treatment programs, and robust policy interventions to mitigate its impact. Regarding Israel, numerous reports highlight a steady increase since 2000 in prescription opioid use and the shift to more potent opioids particularly fentanyl, particularly among more marginalized population groups. In response to growing concern in the country about the rise in prescription opioid use and the consequential risk of opioid use disorder, the Israeli government, together with the country's health service providers, implemented a series of measures to monitor and regulate opioid prescriptions and balance the need for effective pain management with the prevention of opioid abuse and its associated harms. A national opioid data monitoring system is being established, alongside the provision of addiction training for health professionals, the integration of treatment services for opioid use disorder into the nationalized primary healthcare system, and the expansion of harm reduction strategies to mitigate the health risks associated with opioid use. Additional funding for opioid-related research, and for the broader fields of addictions and mental health, is vital. In conclusion, the sum of the evidence suggests that Israel is not facing an "opioid crisis" Continued commitment, resources, and innovative approaches will be crucial to ensure that the rising tide of opioid use in Israel, particularly during and in the aftermath of the ongoing war, will not become a tidal wave.

Slow dissociation kinetics of fentanyls and nitazenes correlates with reduced sensitivity to naloxone reversal at the µ-opioid receptor.

BACKGROUND AND PURPOSE: Fentanyls and nitazenes are µ-opioid receptor agonists responsible for a large number of opioid overdose deaths. Here, we determined the potency, dissociation kinetics and antagonism by naloxone at the µ receptor of several fentanyl and nitazene analogues, compared to morphine and DAMGO. EXPERIMENTAL APPROACH: In vitro assays of G protein activation and signalling and arrestin recruitment were performed. AtT20 cells expressing µ receptors were loaded with a membrane potential dye and changes in fluorescence used to determine agonist potency, dissociation kinetics and susceptibility to antagonism by naloxone. BRET experiments were undertaken in HEK293T cells expressing µ receptors to assess Gi protein activation and ß-arrestin 2 recruitment. KEY RESULTS: The apparent rate of agonist dissociation from the µ receptor varied: morphine, DAMGO, alfentanil and fentanyl dissociated rapidly, whereas isotonitazene, etonitazene, ohmefentanyl and carfentanil dissociated slowly. Slowly dissociating agonists were more resistant to antagonism by naloxone. For carfentanil, the slow apparent rate of dissociation was not because of G protein receptor kinase-mediated arrestin recruitment as its apparent rate of dissociation was not increased by inhibition of G protein-coupled receptor kinases (GRKs) with Compound 101. The in vitro relative potencies of fentanyls and nitazenes compared to morphine were much lower than that previously observed in in vivo experiments. CONCLUSIONS AND IMPLICATIONS: With fentanyls and nitazenes that slowly dissociate from the µ receptor, antagonism by naloxone is pseudo-competitive. In overdoses involving fentanyls and nitazenes, higher doses of naloxone may be required for reversal than those normally used to reverse heroin overdose.

Dexmedetomidine Versus Fentanyl on Time to Extubation in Patients with Morbid Obesity Undergoing Laparoscopic Sleeve Gastrectomy.

Background: Sleeve gastrectomy (SG) is an effective method for managing obesity. While opioids are used for their hemodynamic stability and their ability to reduce intraoperative stress, they also have reported side effects. Dexmedetomidine (DEX), an α2 adrenergic receptor agonist, is noted for its analgesic and anesthetic-sparing effects, leading to a higher quality of recovery. Objectives: The study aims to compare the effects of fentanyl and dexmedetomidine (DEX) on the recovery of morbidly obese patients following laparoscopic sleeve gastrectomy (SG). Methods: This randomized, double-blind study involved 64 patients, equally divided into two groups. The Dexmedetomidine group (Group D) received an intravenous (IV) loading dose of dexmedetomidine (1 µg/kg) over 15 minutes before anesthesia induction, followed by a 10 mL saline 0.9% infusion over 60 seconds during induction. Post-intubation, dexmedetomidine was administered at 0.5 µg/kg/h. The Fentanyl group (Group F) received a volume-matched saline 0.9% IV over 15 minutes pre-induction and fentanyl (1 µg/kg) diluted in 10 ml saline 0.9% IV over 60 seconds during induction. After intubation, a continuous fentanyl infusion was maintained at a rate of 1 µg/kg/hr. Results: Extubation time was significantly shorter in the Dexmedetomidine group (Group D) at 8.25 ± 2.7 minutes compared to the Fentanyl group (Group F) at 10.47 ± 2.17 minutes, with a P-value of 0.001. Intraoperative heart rate and mean arterial blood pressure were also significantly lower in Group D than in Group F. Visual analogue scale (VAS) pain scores were significantly lower in Group D compared to Group F upon arrival at the post-anesthesia care unit and at 2 hours postoperatively (P-value < 0.05). Additionally, the morphine dose consumed in the first 12 hours after surgery was significantly lower in Group D (5.75 ± 2.20 mg) compared to Group F (8 ± 2.38 mg), with a P-value of 0.001. Conclusions: For morbidly obese patients undergoing laparoscopic sleeve gastrectomy, dexmedetomidine (DEX) proves to be an effective anesthetic choice. It not only reduces extubation time but also lowers early postoperative visual analogue scale (VAS) pain scores and opioid consumption within the first 12 hours following surgery.

In vivo pharmacokinetic, pharmacodynamic and brain concentration comparison of fentanyl and para-fluorofentanyl in rats.

In 2022, para-fluorofentanyl (pFF) rose to the 6th most reported drug and the most reported fentanyl analog in the United States according to the Drug Enforcement Administration (DEA). pFF differs from fentanyl by the addition of a single fluorine group. To date, pFF has not been extensively evaluated in vivo and is frequently seen in combination with fentanyl. In the present study, the pharmacodynamic (PD) and pharmacokinetic (PK) properties and brain region-specific concentrations of pFF were evaluated in male Sprague-Dawley rats and compared to fentanyl. A 300 µg/kg subcutaneous dose of fentanyl or pFF was administered to assess PD and PK parameters as well as brain region concentrations. PD parameters were evaluated via a tail flick test to evaluate analgesia and core body temperature to measure hypothermia, a surrogate marker of overall opioid toxicity. Fentanyl and pFF were found to be equally active at the tested dose in terms of tail flick response with both compounds producing an analgesic response that lasted up to 240 min post-drug treatment. pFF induced a significantly greater hypothermic effect compared to fentanyl with a maximum temperature decrease of -5.6 ℃. Plasma PK parameters (T1/2, AUC, etc.) did not differ between fentanyl and pFF. However, pFF concentrations in the medulla, hippocampus, frontal cortex and striatum were more than two times the fentanyl concentrations. The increase in brain concentrations and greater hypothermic effect suggests that pFF is potentially more dangerous than fentanyl.

Assessment of the antinociceptive effect of a single fentanyl bolus dose in children: A pharmacokinetic and pharmacodynamic analysis based on the nociception level index during sevoflurane general anesthesia.

BACKGROUND: The Nociception Level Index has shown benefits in estimating the nociception/antinociception balance in adults, but there is limited evidence in the pediatric population. Evaluating the index performance in children might provide valuable insights to guide opioid administration. AIMS: To evaluate the Nociception Level Index ability to identify a standardized nociceptive stimulus and the analgesic effect of a fentanyl bolus. Additionally, to characterize the pharmacokinetic/pharmacodynamic relationship of fentanyl with the Nociception Level Index response during sevoflurane anesthesia. METHODS: Nineteen children, 5.3 (4.1-6.7) years, scheduled for lower abdominal or urological surgery, were studied. After sevoflurane anesthesia and caudal block, a tetanic stimulus (50 Hz, 60 mA, 5 s) was performed in the forearm. Following the administration of fentanyl 2 µg/kg intravenous bolus, three similar consecutive tetanic stimuli were performed at 5-, 15-, and 30-min post-fentanyl administration. Changes in the Nociception Level Index, heart rate, mean arterial pressure, and bispectral index were compared in response to the tetanic stimuli. Fentanyl plasma concentrations and the Nociception Level Index data were used to elaborate a pharmacokinetic/pharmacodynamic model using a sequential modeling approach in NONMEM®. RESULTS: After the first tetanic stimulus, both the Nociception Level Index and the heart rate increased compared to baseline (8 ± 7 vs. 19 ± 10; mean difference (CI95) -12(-18--6) and 100 ± 10 vs. 102 ± 10; -2(-4--0.1)) and decrease following fentanyl administration (19 ± 10 vs. 8 ± 8; 12 (5-18) and 102 ± 10 vs. 91 ± 11; 11 (7-16)). In subsequent tetanic stimuli, heart rate remained unchanged, while the Nociception Level Index progressively increased within 15 min to values similar to those before fentanyl. An allometric weight-scaled, 3-compartment model best characterized the pharmacokinetic profile of fentanyl. The pharmacokinetic/pharmacodynamic modeling analysis revealed hysteresis between fentanyl plasma concentrations and the Nociception Level Index response, characterized by plasma effect-site equilibration half-time of 1.69 (0.4-2.9) min. The estimated fentanyl C50 was 1.93 (0.73-4.2) ng/mL. CONCLUSION: The Nociception Level Index showed superior capability compared to traditional hemodynamic variables in discriminating different nociception-antinociception levels during varying fentanyl concentrations in children under sevoflurane anesthesia.