Manifestaciones clínicas post supresión de sedoanalgesia en pacientes adultos de una terapia intensiva / Clinical manifestations after suppression of sedoanalgesia in adult patients in intensive care

Introducción: en la unidad de cuidados intensivos (UCI), las personas asistidas con patologías relevantes se encuentran bajo sedación, una vez que estas se encuentran bajo los principios de supresión de la sedación, es importante identificar cuáles son las manifestaciones que presentan, propias de las sedaciones. Objetivo: describir las manifestaciones clínicas del síndrome de supresión de la sedoanalgesia presentes en pacientes asistidos en un Hospital Público de la Ciudad de Corrientes de enero a diciembre del 2022. Metodología: estudio cuantitativo, descriptivo, transversal y observacional. La muestra incluyó pacientes adultos de UCI. El cálculo del tamaño muestral se realizó a través del método probabilístico aleatorio simple resultando de éste una muestra de 100 historias clínicas. Para la recolección de datos se utilizó la observación y como instrumento un formulario semiestructurado, de carácter anónimo. Cada formulario contenía datos específicos donde se categorizan las variables en estudio como ser edad, sexo, comorbilidades, tiempo de sedoanalgesia, tipo de sedación, sedoanalgesia utilizada, agitación, confusión, alucinación, diaforesis, taquicardia. Resultados: en cuanto a la edad se obtuvo un promedio de 49 años, el sexo predominante fue el masculino con 52%, en cuanto a las comorbilidades más frecuentes, el 20% presentó Insuficiencia Respiratoria Aguda y el 16% Insuficiencia renal. El motivo de ingreso a UCI en mayor medida con el 33% fue por dificultad respiratoria y Post Quirúrgicos complicados 32%. Los fármacos de mayor elección fueron midazolam 94%, seguido del fentanilo 80%. En cuanto al tiempo de sedación de los pacientes, se encontró una media de 1265 horas. Las manifestaciones clínicas que se observaron en la muestra en mayor medida corresponden a taquicardia 70%, agitación 52%, un 37% confusión e hipertensión y un 24% alucinación. Conclusión: las manifestaciones que se presentaron con mayor frecuencia fueron taquicardia, agitación, confusión, hipertensión y con menor frecuencia alucinación[AU]

Introduction: in the intensive care unit (ICU), people treated with relevant pathologies are under sedation. Once they are under the principles of sedation suppression, it is important to identify the manifestations they present, typical of sedations. Objective: To describe the clinical manifestations of sedation suppression syndrome present in patients treated at a Public Hospital in the City of Corrientes from January to December 2022. Methodology: quantitative, descriptive, cross-sectional and observational study. The sample included adult ICU patients. The calculation of the sample size was carried out through the simple random probabilistic method, resulting in a sample of 100 medical records. Manifestaciones clínicas post supresión de sedoanalgesia en pacientes adultos de una terapia intensiva. Observation was used to collect data and a semi-structured, anonymous form was used as an instrument. Each form contained specific data where the variables under study were categorized, such as age, sex, comorbidities, sedation time, type of sedation, sedation used, agitation, confusion, hallucination, diaphoresis, tachycardia. Results: regarding age, an average of 49 years was obtained, the predominant sex was male with 52%, regarding the most frequent comorbidities, 20% presented Acute Respiratory Failure and 16% Renal failure. The reason for admission to the ICU to a greater extent with 33% was due to respiratory difficulty and complicated Post-Surgeries 32%. The drugs of greatest choice were midazolam 94%, followed by fentanyl 80%. Regarding the sedation time of the patients, an average of 1265 hours was found. The clinical manifestations that were observed in the sample to a greater extent correspond to tachycardia 70%, agitation 52%, confusion and hypertension 37% and hallucination 24%. Conclusion: the manifestations that occurred most frequently were tachycardia, agitation, confusion, hypertension and, less frequently, hallucination[AU]

Introdução: na unidade de terapia intensiva (UTI), as pessoas tratadas com patologias relevantes estão sob sedação. Uma vez sob os princípios da supressão da sedação, é importante identificar as manifestações que apresentam, típicas das sedações. Objetivo: Descrever as manifestações clínicas da síndrome de supressão da sedação presentes em pacientes atendidos em um Hospital Público da Cidade de Corrientes no período de janeiro a dezembro de 2022. Metodologia: estudo quantitativo, descritivo, transversal e observacional. A amostra incluiu pacientes adultos internados em UTI. O cálculo do tamanho amostral foi realizado pelo método probabilístico aleatório simples, resultando em uma amostra de 100 prontuários. A observação foi utilizada para a coleta de dados e um formulário semiestruturado e anônimo foi utilizado como instrumento. Cada formulário continha dados específicos onde foram categorizadas as variáveis em estudo, como idade, sexo, comorbidades, tempo de sedação, tipo de sedação, sedação utilizada, agitação, confusão, alucinação, sudorese, taquicardia. Resultados: em relação à idade obteve-se uma média de 49 anos, o sexo predominante foi o masculino com 52%, quanto às comorbidades mais frequentes, 20% apresentavam Insuficiência Respiratória Aguda e 16% Insuficiência Renal. O motivo de internação na UTI em maior proporção com 33% foi por dificuldade respiratória e pós-cirúrgicos complicados 32%. Os medicamentos de maior escolha foram midazolam 94%, seguido de fentanil 80%. Quanto ao tempo de sedação dos pacientes, foi encontrada uma média de 1265 horas. As manifestações clínicas mais observadas na amostra correspondem a taquicardia 70%, agitação 52%, confusão e hipertensão 37% e alucinação 24%. Conclusão: as manifestações que ocorreram com maior frequência foram taquicardia, agitação, confusão, hipertensão e, menos frequentemente, alucinação[AU]

Is personal physiology-based rapid prediction digital twin for minimal effective fentanyl dose better than standard practice: a pilot study protocol.

INTRODUCTION: Patients with advanced cancer frequently suffer from chronic, severe disabling pain. Opioids such as morphine and fentanyl are commonly used to manage this pain. Transdermal drug delivery systems are important technologies for administering drugs in a non-invasive, continuous and controlled manner. Due to the narrow therapeutic range of fentanyl, individualised dosing is essential to avoid underdosing or overdosing. Standard clinical calculation tools for opioid rotation however do not include important patient characteristics that account for interindividual variability of opioid pharmacology. METHODS AND ANALYSIS: We developed a clinical protocol to optimise individual fentanyl dosing in patients with advanced cancer switching from oral or intravenous opioids to transdermal fentanyl by using a physics-based digital twin (DT) that is fed by important clinical and physiological parameters. Individual tailoring of transdermal fentanyl therapy is an approach with the potential for personalised and effective care with an improved benefit-risk ratio. However, clinical validation of physics-based digital twins (PBDT) dosing is crucial to proving clinical benefit.Therapeutic drug monitoring will allow to validate the accuracy of PBDT predictions. Additional monitoring for breathing dynamics, sequential pain levels and fentanyl-related adverse events will contribute to evaluating the performance of PBDT-based dosing of transdermal fentanyl. The primary objective of the study is to develop an experimental protocol to validate DT-guided fentanyl dosing in patients with advanced cancer. This clinical study will bring individualised opioid dosing closer to clinical practice. ETHICS AND DISSEMINATION: Study documents have been approved by the responsible Ethics Committee and study initiation is planned for late summer 2024. Data will be shared with the scientific community no more than 1 year following completion of the study and data assembly.

A study comparing brain wave patterns of fentanyl and ketamine in adult patients undergoing minimally invasive surgery.

This study aimed to investigate and compare the neurophysiological impacts of two widely used anesthetic agents, Fentanyl and Ketamine, on EEG power spectra during different stages of anesthesia in adult patients undergoing minimally invasive surgery. EEG data were collected from patients undergoing anesthesia with either Fentanyl or Ketamine. The data were analyzed for relative power spectrum and fast-to-slow wave power ratios, alongside Spectral Edge Frequency 95% (SEF95), at 3 key stages: pre-anesthesia, during stable anesthesia, and post-anesthesia. EEG Relative Power Spectrum: Initially, both groups exhibited similar EEG spectral profiles, establishing a uniform baseline (P > .05). Upon anesthesia induction, the Fentanyl group showed a substantial increase in delta band power (P < .05), suggesting deeper anesthesia, while the Ketamine group maintained higher alpha and beta band activity (P < .05), indicative of a lighter sedative effect. Fast and Slow Wave Power Ratios: The Fentanyl group exhibited a marked reduction in the fast-to-slow wave power ratio during anesthesia (P < .05), persisting post-anesthesia (P < .05) and indicating a lingering effect on brain activity. Conversely, the Ketamine group demonstrated a more stable ratio (P > .05), conducive to settings requiring rapid cognitive recovery. Spectral Edge Frequency 95% (SEF95): Analysis showed a significant decrease in SEF95 values for the Fentanyl group during anesthesia (P < .05), reflecting a shift towards lower frequency power. The Ketamine group experienced a less pronounced decrease (P > .05), maintaining a higher SEF95 value that suggested a lighter level of sedation. The study highlighted the distinct impacts of Fentanyl and Ketamine on EEG power spectra, with Fentanyl inducing deeper anesthesia as evidenced by shifts towards lower frequency activity and a significant decrease in SEF95 values. In contrast, Ketamine's preservation of higher frequency activity and more stable SEF95 values suggests a lighter, more dissociative anesthetic state. These findings emphasize the importance of EEG monitoring in anesthesia for tailoring anesthetic protocols to individual patient needs and optimizing postoperative outcomes.

Efficacy and safety of fentanyl inhalant for the treatment of breakthrough cancer pain: a multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Breakthrough cancer pain (BTcP) has a negative impact on patients' quality of life, general activities, and is related to worse clinical outcomes. Fentanyl inhalant is a hand-held combination drug-device delivery system providing rapid, multi-dose (25µg/dose) administration of fentanyl via inhalation of a thermally generated aerosol. This multicenter, randomized, placebo-controlled, multiple-crossover, double-blind study evaluated the efficacy, safety, and tolerability of fentanyl inhalant in treating BTcP in opioid-tolerant patients. METHODS: The trial was conducted in opioid-tolerant cancer patients with 1 ~ 4 BTcP outbursts per day. Each patient was treated and observed for 6 episodes of BTcP (4 with fentanyl inhalant, 2 with placebo). During each episode of targeted BTcP, patients were allowed up to six inhalations, with an interval of at least 4 min between doses. Primary outcome was the time-weighted sum of PID (pain intensity difference) scores at 30 min (SPID30). RESULTS: A total of 335 BTcP episodes in 59 patients were treated. The mean SPID30 was -97.4 ± 48.43 for fentanyl inhalant-treated episodes, and -64.6 ± 40.25 for placebo-treated episodes (p < 0.001). Significant differences in PID for episodes treated with fentanyl inhalant versus placebo was seen as early as 4 min and maintained for up to 60 min. The percentage of episodes reported PI (pain intensity) scores ≤ 3, a ≥ 33% or ≥ 50% reduction in PI scores at 30 min, PR30 (pain relief scores at 30 min) and SPID60 favored fentanyl inhalant over placebo. Only 4.4% of BTcP episodes required rescue medication in fentanyl inhalant group. Most AEs were of mild or moderate severity and typical of opioid drugs. CONCLUSION: Treatment with fentanyl inhalant was shown to be a promising therapeutic option for BTcP, with significant pain relief starting very soon after dosing. Confirmation of effectiveness requires a larger phase III trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05531422 registered on 6 September 2022 after major amendment, NCT04713189 registered on 14 January 2021.

Remifentanil Target-controlled Infusion Versus Standard of Care for Conscious Sedation During Ultrasound-guided Transbronchial Needle Aspiration and Biopsy: A Randomized, Prospective, Control Study.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure that has become an important tool in the diagnosis and staging of mediastinal lymph node lesions in lung cancer. Adequate sedation is an important part of the procedure as it provides patient comfort and potentially increases diagnostic yield. The sedation modality varies among centers and includes moderate sedation/conscious sedation, deep sedation, and general anesthesia. The object of this study will be the evaluation of patient's comfort and level of satisfaction with the involved health care providers (bronchoscopist and anesthesiologist) of remifentanil administration in target-controlled infusion (TCI) for conscious sedation in patients undergoing EBUS­TBNA, with a prospective randomized study design versus the of standard sedation protocol with midazolam and/or fentanest and/or propofol. METHODS: This study was carried out at the "Campus Biomedico di Roma" University Hospital between September 2021 and November 2021, with a total number of 30 patients enrolled who met the eligibility criteria, randomly divided into 2 groups: group 1 "REMIFENTANIL TCI" (experimental group) where the patients performed the EBUS-TBNA procedure under conscious sedation with infusion of remifentanil TCI with a target between 3 ng/mL and 6 ng/mL and group 2 "STANDARD" (control group) with patients undergoing conscious sedation with the association of midazolam and/or fentanest and/or propofol in refracted boluses based on clinical needs. Complications, safety, and level of satisfaction of the operator, the anesthesiologist, and the patient were evaluated. RESULTS: The results show that sedation with remifentanil in TCI can improve the comfort level of patients, reducing the risks associated with the procedure (lower frequency of oversedations and hypotension), allowing for greater intraprocedural safety. Furthermore, the level of satisfaction of the anesthesiologist and that of the operator appears to be significantly higher in the Remifentanil group. CONCLUSION: The execution of a mild to moderate sedation with Remifentanil in TCI in patients undergoing EBUS is safe, tolerated, and allows to obtain greater intraprocedural comfort. Further studies and larger and more representative samples are obviously needed to confirm and strengthen the validity of a remifentanil TCI-based sedation in endoscopic diagnostics.

Drug Decriminalization, Fentanyl, and Fatal Overdoses in Oregon.

Importance: With the implementation of Measure 110 (M110) in 2021, Oregon became the first US state to decriminalize small amounts of any drug for personal use. To date, no analysis of the association of this law with overdose mortality has fully accounted for the introduction of fentanyl-a substance that is known to drive fatal overdose-to Oregon's unregulated drug market. Objective: To evaluate whether the decriminalization of drug possession in Oregon was associated with changes in fatal drug overdose rates after accounting for the rapid spread of fentanyl in Oregon's unregulated drug market. Design, Setting, and Participants: In this cohort study, the association between fatal overdose and enactment of M110 was analyzed using a matrix completion synthetic control method. The control group consisted of the 48 US states and Washington, DC, all of which did not decriminalize drugs. The rapid spread of fentanyl in unregulated drug markets was determined using the state-level percentage of all samples reported to the National Forensic Laboratory Information System that were identified as fentanyl or its analogues. Mortality data were obtained from the Centers for Disease Control and Prevention for January 1, 2008, to December 31, 2022. Data analysis was performed from fall 2023 through spring 2024. Exposures: Measure 110 took effect in Oregon on February 1, 2021. Main Outcomes and Measures: The primary outcome assessed was fatal drug overdose rates per half-year. A changepoint analysis also determined when each state experienced a rapid escalation of fentanyl in its unregulated drug market. Results: In this analysis, rapid spread of fentanyl in Oregon's unregulated drug supply occurred in the first half of 2021, contemporaneous with enactment of M110. A positive crude association was found between drug decriminalization and fatal overdose rate per 100 000 per half year (estimate [SE], 1.83 [0.47]; P < .001). After adjusting for the spread of fentanyl as a confounder, the effect size changed signs (estimate [SE], -0.51 [0.61]; P = .41) and there was no longer an association between decriminalization and overdose mortality in Oregon. Sensitivity analyses were consistent with this result. Conclusions and Relevance: In this cohort study of fatal drug overdose and the spread of fentanyl through Oregon's unregulated drug market, no association between M110 and fatal overdose rates was observed. Future evaluations of the health effects of drug policies should account for changes in the composition of unregulated drug markets.

Correlates of fentanyl preference among people who use drugs in Rhode Island.

BACKGROUND: Fentanyl is increasingly pervasive in the unregulated drug supply and is a driver of drug overdose deaths in the United States. The aims of this study were to characterize and identify correlates of fentanyl preference among people who use drugs (PWUD) in Rhode Island (RI). METHODS: Using bivariate analysis, we examined associations between fentanyl preference and sociodemographic and psychosocial characteristics at baseline among participants enrolled in the RI Prescription Drug and Illicit Drug Study from August 2020-February 2023. Fentanyl preference was operationalized based on responses to a five-point Likert scale: "I prefer using fentanyl or drugs that have fentanyl in them." Participants who responded that they "strongly disagree," "disagree," or were "neutral" with respect to this statement were classified as not preferring fentanyl, whereas participants who responded that they "agree" or "strongly agree" were classified as preferring fentanyl. RESULTS: Among 506 PWUD eligible for inclusion in this analysis, 15% expressed a preference for fentanyl or drugs containing fentanyl as their drug of choice. In bivariate analyses, preference for fentanyl was positively associated with younger age, white race, lifetime history of overdose, history of injection drug use, past month enrollment in a substance use treatment program, past month treatment with medications for opioid use disorder, and preferences for heroin and crystal methamphetamine (all p < 0.05). Descriptive data yielded further insight into reasons for fentanyl preference, the predominant having to do with perceived effects of the drug and desire to avoid withdrawal symptoms. CONCLUSIONS: Only a relatively small subset of study participants preferred drugs containing fentanyl. Given the increased prevalence of fentanyl contamination across substances within the unregulated drug market, the result for PWUD is increasingly less agency with respect to choice of drug; for example, people may be forced to use fentanyl due to restricted supply and the need to mitigate withdrawal symptoms, or may be using fentanyl without intending to do so. Novel and more effective interventions for PWUD, including increased access to age-appropriate harm reduction programs such as fentanyl test strips and overdose prevention centers, are needed to mitigate fentanyl-related harms.

Assessing the clinical advantage of opioid-reduced anesthesia in thoracoscopic sympathectomy: a prospective randomized controlled trial.

BACKGROUND: Opioid-reduced multimodal analgesia has been used clinically for many years to decrease the perioperative complications associated with opioid drugs. We aimed to assess the clinical effects of opioid-reduced anesthesia during thoracoscopic sympathectomy. METHODS: Surgical patients (n = 151) with palmar hyperhidrosis were randomly divided into control (Group C, 73 patients) and test (Group T, 78 patients) groups. All patients were administered general anesthesia using a laryngeal mask. In Group C, patients received propofol, fentanyl, and cisatracurium for anesthesia induction, and maintenance was achieved with propofol and remifentanil, along with mechanical ventilation during the operation. In Group T, anesthesia was induced with propofol, dezocine, and dexmedetomidine (DEX) and maintained with propofol, DEX, and an intercostal nerve block, along with spontaneous breathing throughout the operation. Perioperative complications related to opioid use include hypotension, bradycardia, hypertension, tachycardia, hypoxemia, nausea, vomiting, urine retention, itching, and dizziness were observed. To assess the impact of these complications, we recorded and compared vital signs, blood gas indices, visual analogue scale (VAS) scores, adverse events, and patient satisfaction between the two groups. RESULTS: Perioperative complications related to opioid use were similar between groups. There were no significant differences in the type of perioperative sedation, analgesia index, respiratory and circulatory indicators, blood gas analysis, postoperative VAS scores, adverse reactions, propofol dosage, postoperative recovery time, and patient satisfaction. CONCLUSIONS: In minimally invasive surgeries such as thoracoscopic sympathectomy, opioid-reduced anesthesia was found to be safe and effective; however, this method did not demonstrate clinical advantages. TRIAL REGISTRATION: Chinese Clinical Trial Register: ChiCTR2100055005, on December 30, 2021.

Effect of oxycodone versus fentanyl for patient-controlled intravenous analgesia after laparoscopic hysteromyomectomy: a single-blind, randomized controlled trial.

A single-blind, randomized controlled trial comparing oxycodone and fentanyl for patient-controlled intravenous analgesia (PCIA) after laparoscopic hysteromyomectomy found comparable pain relief between the two groups. The study included 60 participants, with NRS scores for pain at rest and when moving showing no significant differences between oxycodone and fentanyl groups at various time points postoperatively. Self-rating depression scale scores were also similar between the groups at 48 h. However, patients' satisfaction with PCIA was higher in the oxycodone group, with 73.3% reporting being very satisfied compared to 36.7% in the fentanyl group. Additionally, the oxycodone group had fewer incidences of headaches within 48 h postoperatively compared to the fentanyl group. These findings suggest that oxycodone may offer comparable pain relief, higher patient satisfaction, and fewer headaches for patients undergoing laparoscopic hysteromyomectomy compared to fentanyl, making it a suitable option for postoperative pain management in this population.Clinical trial registration number The study was registered with CHICTR.org, ChiCTR2100051924.

Pocket warming of bupivacaine with fentanyl to shorten onset of labor epidural analgesia: A double-blind randomized controlled clinical trial.

Shortening analgesic onset has been researched and it has been documented that prewarming epidural medications to body temperature (37°C) prior to administration increases medication efficacy. Our double-blind randomized controlled trial was designed to investigate if a lower degree of prewarming in providers' pockets could achieve similar results without the need of a bedside incubator. A total of 136 parturients were randomized into either the pocket-warmed group or the room temperature group to receive 10 mL of 0.125% bupivacaine with 2 µg/mL fentanyl epidural bolus at either the 27.8 ±1.7°C or 22.1 ±1.0°C temperatures, respectively. Primary outcome, time to analgesic onset (verbal rating scale pain score ≤ 3) was recorded in 0-, 5-, 10-, 15-, 20-, 30-, and 60-minutes intervals. It was observed that the pocket-warming group (n = 64) and room temperature group (n = 72) had no significant difference of analgesic onset time (median 8 vs. 6.2 minutes; p = 0.322). The incidence of adverse events such as hypotension, fever (≥ 38°C), nausea, vomiting, and number of top-off epidural boluses, as well as patient satisfaction rates and mode of delivery, were not significantly different between the groups as well. Further research is warranted to confirm these findings and explore the impact of different temperatures on analgesic onset time as well as the logistical issues associated with their clinical implementations.

Biological sex modulates the efficacy of 2,5-dimethoxy-4-iodoamphetamine (DOI) to mitigate fentanyl demand.

BACKGROUND: Overdose deaths remain high for opioid use disorder, emphasizing the need to pursue innovative therapeutics. Classic psychedelic drugs that engage many monoamine receptors mitigate opioid use. Here, we tested the hypothesis that the preferential serotonin 5-HT2AR agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) could reduce the demand for fentanyl in a preclinical model of fentanyl self-administration. METHODS: Male and female Sprague-Dawley rats (n = 25-29) were implanted with indwelling jugular catheters and allowed to self-administer fentanyl (3.2µg/kg/infusion). Rats progressed to a novel low price twice within-session threshold procedure where rats sampled the lowest price twice before decreasing the dose of fentanyl by a » log every 10minutes across 11 doses. Once stable, rats were pretreated with saline or DOI (0.01, 0.03, 1mg/kg). Fentanyl consumption was analyzed using an exponentiated demand function to extract the dependent variables, Q0 and α. RESULTS: Male and female rats acquired fentanyl self-administration in the lowest price twice within-session threshold procedure. DOI dose-dependently altered fentanyl intake such that 5-HT2AR activation decreased Q0 in female rats but increased Q0 in male rats. For demand elasticity, DOI increased α in male rats but did not alter α in female rats. DOI did not alter inactive lever presses or latency. CONCLUSION: DOI reduces consumption at minimally constrained costs but did not affect the reinforcement value of fentanyl in female rats. Alternatively, DOI significantly reduced the reinforcement value of fentanyl in male rats. Biological sex alters the therapeutic efficacy of DOI and 5-HT2AR activation sex-dependently alters opioid reinforcement.

Medial prefrontal neuroplasticity during extended-release naltrexone treatment of opioid use disorder - a longitudinal structural magnetic resonance imaging study.

Opioid use disorder (OUD) has been linked to macroscopic structural alterations in the brain. The monthly injectable, extended-release formulation of µ-opioid antagonist naltrexone (XR-NTX) is highly effective in reducing opioid craving and preventing opioid relapse. Here, we investigated the neuroanatomical effects of XR-NTX by examining changes in cortical thickness during treatment for OUD. Forty-seven OUD patients underwent structural magnetic resonance imaging and subjectively rated their opioid craving ≤1 day before (pre-treatment) and 11 ± 3 days after (on-treatment) the first XR-NTX injection. A sample of fifty-six non-OUD individuals completed a single imaging session and served as the comparison group. A publicly available [¹¹C]carfentanil positron emission tomography dataset was used to assess the relationship between changes in cortical thickness and µ-opioid receptor (MOR) binding potential across brain regions. We found that the thickness of the medial prefrontal and anterior cingulate cortices (mPFC/aCC; regions with high MOR binding potential) was comparable between the non-OUD individuals and the OUD patients at pre-treatment. However, among the OUD patients, mPFC/aCC thickness significantly decreased from pre-treatment to on-treatment. A greater reduction in mPFC/aCC thickness was associated with a greater reduction in opioid craving. Taken together, our study suggests XR-NTX-induced cortical thickness reduction in the mPFC/aCC regions in OUD patients. The reduction in thickness does not appear to indicate a restoration to the non-OUD level but rather reflects XR-NTX's distinct therapeutic impact on an MOR-rich brain structure. Our findings highlight the neuroplastic effects of XR-NTX that may inform the development of novel OUD interventions.

Does IV fentanyl, frequently used in emergency departments, change QTC value? A prospective observational study.

BACKGROUND: Fentanyl is an opioid analgesic frequently used in the emergency department (ED) and is usually administered without knowing the QTC values of the patients or being monitored. However, the effect of fentanyl on QTC, prolongation or shortening, has not been elucidated. This study aimed to determine the effect of fentanyl on QTC. METHODS: This is a prospective observational study in the ED of a tertiary hospital on patients who received intravenous fentanyl for procedures other than intubation. ECG was performed before and at 1, 5, 15, 30, and 60 min after the initiation of fentanyl administration, and QTC value was calculated. Primary outcomes were QTC prolongation, defined as an increase in the QTC to ≥ 500 ms or any increase in QTC by ≥ 60 ms. RESULTS: The study included 109 patients. Of these, 60 patients were male, and the median age was 40. Compared with the baseline QTC value, statistically significant prolongation was detected at the 5th, 15th, 30th, and 60th minutes, with the maximum prolongation at 30 min, and the median was 13.08 ms. Most patients with QTC prolongation were female and over 40 years of age. Clinically, none of these patients developed malignant arrhythmias during the 60-minute monitored observation period. CONCLUSION: Fentanyl prolonged the QTC value statistically significantly. Although no patient developed malignant arrhythmia clinically, our results suggest that this QTC-prolonging effect should be considered when using fentanyl in patients at risk of torsades.

Evaluating fentanyl test strips as a harm reduction strategy in rural and urban counties: study protocol for a randomized controlled trial.

BACKGROUND: Opioid-related fatalities are a leading cause of death in Ohio and nationally, with an increasing number of overdoses attributable to fentanyl. Rapid fentanyl test strips can identify fentanyl and some fentanyl analogs in urine samples and are increasingly being used to check illicit drugs for fentanyl before they are used. Fentanyl test strips are a promising harm reduction strategy; however, little is known about the real-world acceptability and impact of fentanyl test strip use. This study investigates fentanyl test strip distribution and education as a harm reduction strategy to prevent overdoses among people who use drugs. METHODS: The research team will recruit 2400 individuals ≥ 18 years with self-reported use of illicit drugs or drugs purchased on the street within the past 6 months. Recruitment will occur at opioid overdose education and naloxone distribution programs in 16 urban and 12 rural Ohio counties. Participating sites will be randomized at the county level to the intervention or non-intervention study arm. A brief fentanyl test strip educational intervention and fentanyl test strips will be provided to participants recruited from sites in the intervention arm. These participants will be eligible to receive additional fentanyl test strips for 2 years post-enrollment. Participants recruited from sites in the non-intervention arm will not receive fentanyl test strip education or fentanyl test strips. All participants will be followed for 2 years post-enrollment using biweekly, quarterly, and 6-month surveys. Primary outcomes include (1) identification of perceived barriers and facilitating factors associated with incorporating fentanyl test strip education and distribution into opioid overdose education and naloxone distribution programs; (2) differences in knowledge and self-efficacy regarding how to test drugs for fentanyl and strategies for reducing overdose risk between the intervention and non-intervention groups; and (3) differences in non-fatal and fatal overdose rates between the intervention and non-intervention groups. DISCUSSION: Findings from this cluster randomized controlled trial will contribute valuable information about the feasibility, acceptability, and impact of integrating fentanyl test strip drug checking in rural and urban communities in Ohio and help guide future overdose prevention interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT05463341. Registered on July 19, 2022. https://clinicaltrials.gov/study/NCT05463341.

[Opioid crisis in the USA: what are implications for Switzerland?] / Crise des opioïdes aux États-Unis : quelles implications pour la Suisse ?

Warnings in Europe signal a rise in illicitly-manufactured fentanyl and other high potency synthetic opioids which could destabilize drug markets, strain health systems, and escalate harms of substance use and death. Here, we provide an overview of fentanyl in North America, drawing implications for Switzerland. Fentanyl withdrawal starts sooner, is more severe, and has worse anxiety and pain. Clinical care includes aggressive use of full agonist opioids, opioid agonist therapies (OAT) and adjunctive medications for acute withdrawal, and a need for low-threshold, readily accessible OAT to engage patients and mitigate harms. The US experience suggests the importance of widespread naloxone distribution, peer-based initiatives, early warning systems, and partnerships across patient-groups, healthcare systems, and public health.

En Europe, des mises en garde signalent une augmentation du fentanyl et d'autres opioïdes de synthèse fabriqués illicitement, qui pourrait déstabiliser le marché des drogues, mettre à rude épreuve le système de santé et augmenter les dommages et le nombre de décès. Nous présentons ici la situation Nord-Américaine et ses implications pour la Suisse. Le sevrage du fentanyl survient tôt, est plus sévère et associé à une aggravation de l'anxiété et de la douleur. La prise en charge comprend l'utilisation agressive d'agonistes opioïdes complets, les traitements agonistes opiacés (TAO) et des médicaments d'appoint. L'expérience américaine montre l'importance d'une distribution généralisée de naloxone, de l'implication des pairs, des systèmes d'alerte précoce, et des partenariats entre les patients, les systèmes de soins et la santé publique.

Preferred pharmaceutical-grade opioids to reduce the use of unregulated opioids: A cross-sectional analysis among people who use unregulated opioids in Vancouver, Canada.

OBJECTIVES: Many people who use drugs in the United States and Canada continue to access the contaminated unregulated drug supply, resulting in the ever-escalating overdose epidemic. In Canada, even in areas where healthcare providers are authorized to prescribe alternatives to the unregulated supply (e.g., prescribed safer supply), availability and accessibility are low. We sought to characterize the needs of people who use unregulated opioids in Vancouver, Canada by asking them whether access to any pharmaceutical opioids would reduce their use of unregulated opioids, and if so, which pharmaceutical opioids they preferred. METHODS: We analyzed data from participants who self-reported using unregulated opioids in three Vancouver-based prospective cohort studies between 2021 and 2022. We employed multivariable logistic regression to identify factors associated with reporting a preferred pharmaceutical opioid to reduce unregulated opioid use. RESULTS: Of 681 eligible participants, 504 (74.0 %) identified a preferred pharmaceutical opioid to reduce unregulated opioid use. The most commonly reported preferred opioids included: diacetylmorphine (42.9 %), fentanyl patches (11.1 %), and fentanyl powder (10.5 %). Overall, 5.6 % of participants who identified diacetylmorphine, 12.5 % of participants who identified fentanyl patches, and no participants who identified fentanyl powder as their preferred opioids reported receiving prescriptions of them. In multivariable analysis, exposure to benzodiazepines through unregulated drug use (adjusted odds ratio [AOR] = 2.57; 95 % confidence interval [CI] = 1.69-3.90), and receipt of prescribed safer supply of opioids without opioid agonist therapy (OAT; AOR = 2.66; 95 % CI = 1.12-6.36) within the past six months were significantly associated with reporting a preferred pharmaceutical opioid. CONCLUSION: Three-quarters of participants reported that receiving prescribed pharmaceutical opioids of their preference could reduce their use of unregulated opioids; however, the proportions of those actually being prescribed their preferred opioids were very low. Further, these participants were also more likely to report exposure to benzodiazepine-adulterated drugs. Our findings provide important implications for future safer supply programs.

CARDIORESPIRATORY EFFECTS OF VATINOXAN IN BLESBOK (DAMALISCUS PYGARGUS PHILLIPSI) IMMOBILIZED WITH THIAFENTANIL-MEDETOMIDINE.

Combinations of a low dose of opioid, such as thiafentanil, and a high dose of medetomidine, are increasingly being used for immobilization of African ungulates. Both drugs can have undesirable cardiorespiratory effects. In this study we assessed whether vatinoxan, a peripherally acting alpha2-adrenergic receptor antagonist, can be used to alleviate some of these effects without affecting the immobilization quality. Eight healthy, female, boma-confined blesbok (Damaliscus pygargus phillipsi), weighing a mean (SDtion) of 56.8 (4.4) kg, were immobilized twice in a randomized cross-over study with a 2-wk washout period using (1) 0.5 mg thiafentanil + 1.5 mg medetomidine (TM), (2) TM + vatinoxan: 0.5 mg thiafentanil + 1.5 mg medetomidine + 15 mg vatinoxan per milligram medetomidine (total of 22.5 mg, administered intramuscularly at 10 min post recumbency). Heart rate, respiratory rate, rectal temperature, oxygen saturation (SpO2), arterial blood pressure, and sedation scores from 1 to 5 (1 = limited effect; 5 = excessively deep) were measured every 5 min. Arterial blood gases (PaO2 and PaCO2) were measured at 10, 15, 25, and 35 min postrecumbency and the alveolar--arterial oxygen gradient (P[A-a]O2) was calculated. Induction times and immobilization quality did not differ between groups. The heart rate was significantly higher and the mean arterial pressure significantly lower in blesbok after receiving vatinoxan. All animals were hypoxemic and there were no significant differences in the respiratory rates, PaO2, PaCO2, SpO2, or P(A-a)O2 gradients at any time point. Although vatinoxan did not improve respiratory variables and blood oxygenation in these animals, the change in cardiovascular variables may suggest that it improves tissue perfusion, a positive outcome that requires further investigation.

Fentanyl induces analgesic effect through miR-381-3p/TRPM7 when combined with bupivacaine in subarachnoid injection.

Fentanyl combined with bupivacaine in subarachnoid anesthesia exerts a strong synergistic analgesic effect, extending the duration of analgesia. However, the mechanism of enhanced analgesic effect of fentanyl remains elusive. The present study investigated the potential mechanism of the analgesic effect of fentanyl when combined with bupivacaine. The subarachnoid injection (SI) rat model was employed, and SI of fentanyl or/and bupivacaine was used to investigate their analgesic effect. Dorsal root ganglion (DRG)' RNA sequencing (RNA-Seq) and bioinformatics analysis were performed to evaluate the downstream mechanisms of MicroRNAs (miRNAs). Further validation tests included RT-PCR, Western blot, and immunofluorescence. A single SI of fentanyl or bupivacaine decreased the positive responses to stimulation when used alone or in combination. RNA-seq results revealed that miR-381-3p played a role in the fentanyl-driven promotion of analgesia. Bioinformatics analysis and dual-luciferase reporter identified TRPM7 as a direct downstream target gene of miR-381-3p. In vitro, overexpression of miR-381-3p could further block fentanyl-induced expression of TRPM7, p-ERK1/2, CGRP, and SP. In addition, antagomir-381-3p reversed the inhibitory effect of fentanyl on the expression of TRPM7, p-ERK1/2, CGRP, and SP, in vivo; however, TRPM7 siRNA rescued the effect of antagomir-381-3p. In conclusion, fentanyl inhibits p-ERK by targeting TRPM7 via miR-381-3p, lowering the production of CGRP and SP, and ultimately inducing analgesic effects.

Bioabsorbable, subcutaneous naltrexone implants mitigate fentanyl-induced respiratory depression at 3 months-A pilot study in male canines.

The aim of this study is to determine if extended-release, bioabsorbable, subcutaneous naltrexone (NTX) implants can mitigate respiratory depression after an intravenous injection (IV) of fentanyl. Six different BIOabsorbable Polymeric Implant Naltrexone (BIOPIN) formulations, comprising combinations of Poly-d,l-Lactic Acid (PDLLA) and/or Polycaprolactone (PCL-1 or PCL-2), were used to create subcutaneous implants. Both placebo and naltrexone implants were implanted subcutaneously in male dogs. The active naltrexone implants consisted of two doses, 644 mg and 1288 mg. A challenge with IV fentanyl was performed in 33 male dogs at 97-100 days after implantation. Following the administration of a 30 µg/kg intravenous fentanyl dose, the placebo cohort manifested a swift and profound respiratory depression with a ~50% reduction in their pre-dose respiratory rate (RR). The BIOPIN NTX-implanted dogs were exposed to escalating doses of intravenous fentanyl (30 µg/kg, 60 µg/kg, 90 µg/kg, and 120 µg/kg). In contrast, the dogs implanted with the BIOPIN naltrexone implants tolerated doses up to 60 µg/kg without significant respiratory depression (<50%) but had severe respiratory depression with fentanyl doses of 90 µg/kg and especially at 120 µg/kg. Bioabsorbable, extended-release BIOPIN naltrexone implants are effective in mitigating fentanyl-induced respiratory depression in male canines at about 3 months after implantation. This technology may also have potential for mitigating fentanyl-induced respiratory depression in humans.