Burden of opioid toxicity death in the fentanyl-dominant era for people who experience incarceration in Ontario, Canada, 2015-2020: a whole population retrospective cohort study.

OBJECTIVES: To describe mortality due to opioid toxicity among people who experienced incarceration in Ontario between 2015 and 2020, during the fentanyl-dominant era. DESIGN: In this retrospective cohort study, we linked Ontario coronial data on opioid toxicity deaths between 2015 and 2020 with correctional data for adults incarcerated in Ontario provincial correctional facilities. SETTING: Ontario, Canada. PARTICIPANTS: Whole population data. MAIN OUTCOMES AND MEASURES: The primary outcome was opioid toxicity death and the exposure was any incarceration in a provincial correctional facility between 2015 and 2020. We calculated crude death rates and age-standardised mortality ratios (SMR). RESULTS: Between 2015 and 2020, 8460 people died from opioid toxicity in Ontario. Of those, 2207 (26.1%) were exposed to incarceration during the study period. Among those exposed to incarceration during the study period (n=1 29 152), 1.7% died from opioid toxicity during this period. Crude opioid toxicity death rates per 10 000 persons years were 43.6 (95% CI=41.8 to 45.5) for those exposed to incarceration and 0.95 (95% CI=0.93 to 0.97) for those not exposed. Compared with those not exposed, the SMR for people exposed to incarceration was 31.2 (95% CI=29.8 to 32.6), and differed by sex, at 28.1 (95% CI=26.7 to 29.5) for males and 77.7 (95% CI=69.6 to 85.9) for females. For those exposed to incarceration who died from opioid toxicity, 10.6% died within 14 days of release and the risk was highest between days 4 and 7 postrelease, at 288.1 per 10 000 person years (95% CI=227.8 to 348.1). CONCLUSIONS: The risk of opioid toxicity death is many times higher for people who experience incarceration compared with others in Ontario. Risk is markedly elevated in the week after release, and women who experience incarceration have a substantially higher SMR than men who experience incarceration. Initiatives to prevent deaths should consider programmes and policies in correctional facilities to address high risk on release.

Using Social Media to Examine Themes Surrounding Fentanyl Misuse and Risk Indicators.

Background: Opioid misuse is a crisis in the United States, and synthetic opioids such as fentanyl pose risks for overdose and mortality. Individuals who misuse substances commonly seek information and support online due to stigma and legal concerns, and this online networking may provide insight for substance misuse prevention and treatment. We aimed to characterize topics in substance-misuse related discourse among members of an online fentanyl community. Method: We investigated posts on a fentanyl-specific forum on the platform Reddit to identify emergent substance misuse-related themes potentially indicative of heightened risk for overdose and other adverse health outcomes. We analyzed 27 posts and 338 comments with a qualitative codebook established using a subset of user posts via inductive and deductive methods. Posts and comments were independently reviewed by two coders with a third coder resolving discrepancies. The top 200 subreddits with the most activity by r/fentanyl members were also inductively analyzed to understand interests of r/fentanyl users. Results: Functional/quality of life impairments due to substance misuse (29%) was the most commonly occurring theme, followed by polysubstance use (27%) and tolerance/dependence/withdrawal (20%). Additional themes included drug identification with photos, substances cut with other drugs, injection drugs, and past overdoses. Media-focused subreddits and other drug focused communities were among the communities most often followed by r/fentanyl users. Conclusion: Themes closely align with DSM-V substance use disorder symptoms for fentanyl and other substances. High involvement in media-focused subreddits and other substance-misuse-related communities suggests digital platforms as acceptable for overdose prevention and recovery support interventions.

Incidence of Precipitated Withdrawal During a Multisite Emergency Department-Initiated Buprenorphine Clinical Trial in the Era of Fentanyl.

This cohort study examines the incidence of precipitated withdrawal comparing traditional sublingual buprenorphine with a 7-day extended-release injectable initiated in the emergency department (ED).

The pattern of brain oxygen response induced by intravenous fentanyl limits the time window of therapeutic efficacy of naloxone.

Opioids induce respiratory depression resulting in coma or even death during overdose. Naloxone, an opioid antagonist, is the gold standard reversal agent for opioid intoxication, but this treatment is often less successful for fentanyl. While low dosing is thought to be a factor limiting naloxone's efficacy, the timing between fentanyl exposure and initiation of naloxone treatment may be another important factor. Here, we used oxygen sensors coupled with amperometry to examine the pattern of oxygen responses in the brain and periphery induced by intravenous fentanyl in freely moving rats. At both doses (20 and 60 µg/kg), fentanyl induced a biphasic brain oxygen response-a rapid, strong, and relatively transient decrease (8-12 min) followed by a weaker and prolonged increase. In contrast, fentanyl induced stronger and more prolonged monophasic oxygen decreases in the periphery. When administered before fentanyl, intravenous naloxone (0.2 mg/kg) fully blocked the hypoxic effects of moderate-dose fentanyl in both the brain and periphery. However, when injected 10 min after fentanyl, when most of hypoxia had already ceased, naloxone had minimal effect on central and peripheral oxygen levels, but at a higher dose, it strongly attenuated hypoxic effects in the periphery with only a transient brain oxygen increase associated with behavioral awakening. Therefore, due to the rapid, strong but transient nature of fentanyl-induced brain hypoxia, the time window when naloxone can attenuate this effect is relatively short. This timing limitation is critical, making naloxone most effective when used quickly and less effective when used during the post-hypoxic comatose state after brain hypoxia has already ceased and harm for neural cells already done.

Medetomidine/midazolam/fentanyl narcosis alters cardiac autonomic tone leading to conduction disorders and arrhythmias in mice.

Arrhythmias are critical contributors to cardiovascular morbidity and mortality. Therapies are mainly symptomatic and often insufficient, emphasizing the need for basic research to unveil the mechanisms underlying arrhythmias and to enable better and ideally causal therapies. In translational approaches, mice are commonly used to study arrhythmia mechanisms in vivo. Experimental electrophysiology studies in mice are performed under anesthesia with medetomidine/midazolam/fentanyl (MMF) and isoflurane/fentanyl (IF) as commonly used regimens. Despite evidence of adverse effects of individual components on cardiac function, few data are available regarding the specific effects of these regimens on cardiac electrophysiology in mice. Here we present a study investigating the effects of MMF and IF narcosis on cardiac electrophysiology in vivo in C57BL/6N wild-type mice. Telemetry transmitters were implanted in a group of mice, which served as controls for baseline parameters without narcosis. In two other groups of mice, electrocardiogram and invasive electrophysiology studies were performed under narcosis (with either MMF or IF). Basic electrocardiogram parameters, heart rate variability parameters, sinus node and atrioventricular node function, and susceptibility to arrhythmias were assessed. Experimental data suggest a remarkable influence of MMF on cardiac electrophysiology compared with IF and awake animals. While IF only moderately reduced heart rate, MMF led to significant bradycardia, spontaneous arrhythmias, heart rate variability alterations as well as sinus and AV node dysfunction, and increased inducibility of ventricular arrhythmias. On the basis of these observed effects, we suggest avoiding MMF in mice, specifically when studying cardiac electrophysiology, but also whenever a regular heartbeat is required for reliable results, such as in heart failure or imaging research.

Comparation Among Opioid-Based, Low Opioid and Opioid Free Anesthesia in Colorectal Oncologic Surgery.

Introduction: Opioids are the "gold standard" for pain treatment during and after colorectal surgery. They can inhibit cellular and humoral immunity and it is assumed that can promote cancer cell proliferation and metastatic spread. Adequate pain management can be achieved not only with opioids, but also with non-opioid drugs, which can be used together in small doses, i.e., multimodal analgesia, and can lower the need for opioids during and after surgery. Opioid free anesthesia (OFA) is part of multimodal analgesia, where opioids are not used in the intraoperative period. Materials and methods: In this prospective and randomized clinical study 60 patients scheduled for open colorectal surgery were enrolled. They were between the ages of 45 and 70 with the American Association of Anesthesiologists (ASA) classifications 1, 2 and 3, divided in three groups. The first group of patients, or Opioid-based anesthesia group (OBAG), received the following for induction to anesthesia: lidocaine at 1 mg/kg, fentanyl 100 at µgr, propofol at 2mg/kg and rocuronium bromide at 0.6 mg/kg. They intermittently received 50-100 µgr fentanyl intravenously and 0.25 % bupivacaine 2-3 ml every 30-45 minutes, given in the epidural catheter during surgery. The second group of patients, or Low opioid anesthesia group (LOAG), received the following for induction to anesthesia: lidocaine at 1 mg/kg, fentanyl at 100 µgr, propofol at 2mg/kg and rocuronium bromide at 0.6 mg/kg. Prior to surgery, 50 µgr of fentanyl with 5 ml 0.25% bupivacaine was given into the epidural catheter, and the same dose was received at the end of surgery. The third group, or Opioid free anesthesia group (OFAG), received the following before the induction to general anesthesia: dexamethasone at 0.1 mg/kg and 1 gr of paracetamol. Induction to general anesthesia was with lidocaine at 1 mg/kg, propofol at 2mg/kg, ketamine at 0.5 mg/kg and rocuronium bromide at 0.6 mg/kg. After intubation, intravenous continuous infusion with lidocaine was at 2 mg/kg/h, ketamine 0.2 mg/kg/h and magnesium 15 mg/kg/h loaded on and intermittently 0.25 % bupivacaine 2-3 ml every 30-45 minutes given in the epidural catheter during surgery. The primary goal was to measure the patients' pain after the first 72 postoperative hours in all three groups (2, 6, 12, 24, 36, 48 and 72 hours after surgery). The secondary goal was to measure the total amount of morphine given in the epidural catheter in the postoperative period in all three groups. Other secondary goals were: to compare the total amount of fentanyl given intravenously during surgery in the first and second groups, determine if there was a need to use rescue analgesia in the postoperative period, measure the occurrence of PONV, and to measure the total amount of bupivacaine given in the epidural catheter during operation in all three groups. Results: Visual Analogue Scale (VAS) score comparisons between groups showed patients from the OBA and LOA groups had significantly higher VAS scores, compared to the patients from the OFA group 2, 12, 24 and 48 hours after operation. After 6 hours postoperatively, patients from the LOA group had significantly higher VAS scores, compared to patients from the OBA and OFA groups. After 36 hours postoperatively, patients from the OBA group had significantly higher VAS scores compared to patients from the LOA and OFA groups. At the last follow-up point, 72 hours after the intervention, the patients from the OBA and LOA groups had significantly higher VAS scores compared to the patients from the OFA group. All patients from the OBA and LOA groups, and only 9 from the OFA group received morphine in the postoperative period via epidural catheter. Patients from the Opioid group received significantly higher amounts of fentanyl during surgery. Additional administration of another analgesic drug in the postoperative period was prescribed in 55% of patients in the OBAG, in 50% in the LOAG and in 35% of the OFA group. PONV was registered in 60% of patients from the OBAG and in 40% of patients from the LOAG. In the OFA group did not register PONV in any of the patients. The biggest amount of bupivacaine given during surgery was in the OBAG (26.37 ± 2.6 mg), in LOAG was 25.0 ± 0 and the less in OFAG group (24.50 ± 4.3). Conclusion: Patients from OFA group, compared with patients from OBAG and LOAG, have the lowest pain score in first 72 hours after open colorectal surgery, received fewer opioids via an epidural catheter in the postoperative period, had less need for rescue analgesia, no occurrence of PONV, and less need for bupivacaine via an epidural catheter in the intraoperative period.

Safety of rapid inpatient methadone initiation protocol: A retrospective cohort study.

BACKGROUND: Current methadone titration guidelines recommend low initial doses (15-40 mg) and slow increases (10-20 mg every 3 to 7 days) to prevent dose accumulation and oversedation until reaching a target therapeutic dose between 60 and 120 mg. These guidelines were created primarily for outpatient settings in the pre-fentanyl era. Methadone initiations are becoming more common in hospitals, but no titration guidelines exist specific to this treatment setting, which has capacity for increased monitoring. Our objective was to assess the safety of rapid inpatient methadone initiation with regard to mortality, overdose, and serious adverse outcomes both in-hospital and postdischarge. METHODS: This is a retrospective, observational, cohort study conducted at an urban, academic medical center in the United States. We queried our electronic medical record for hospitalized adults with moderate to severe opioid use disorder admitted between July 1, 2018, and November 30, 2021. Included patients were rapidly initiated on methadone with 30 mg as the initial dose and 10 mg increases daily until reaching 60 mg. The study extracted thirty-day post-discharge opioid overdose and mortality data from the CRISP database. RESULTS: Twenty-five hospitalized patients received rapid methadone initiation during the study period. The study had no major adverse events including in-hospital or thirty-day post-discharge overdoses or deaths. The study did have two instances of sedation, but neither led to methadone dose holds. There were no instances of QTc prolongation. The study had one patient-directed discharge. CONCLUSIONS: This study demonstrated that a small subset of hospitalized patients tolerated rapid methadone initiation. More rapid titrations can be utilized in a monitored inpatient setting to retain patients in the hospital and allow providers to account for increased tolerance in the fentanyl era. Guidelines should be updated to reflect the capabilities of inpatient settings to safely initiate and rapidly titrate methadone. Further work should determine optimal methadone initiation protocols in the fentanyl era.

Illicit Fentanyl Exposure Among Victims of Violence Treated at a Trauma Center.

INTRODUCTION: Opioid overdoses and violent injury are leading causes of death in the United States, yet testing for novel opioids like fentanyl remains uncommon. The purpose of this investigation is to characterize a population of victims of violence who test positive for illicit fentanyl. METHODS: Retrospective cohort study of patients treated at a level-one trauma center between January 31, 2019 and February 21, 2020. Data were extracted from the electronic medical record. Subjects were included if they had an encounter diagnosis for a violent or intentional injury, using the International Classification of Diseases, v10 (X92-Y09). We excluded patients who received licit fentanyl as a part of their care before testing. Those who tested positive for fentanyl exposure on our standard hospital urine drug screen were considered to have been exposed to illicit fentanyl. Those testing negative for fentanyl were considered controls. RESULTS: Of the 1132 patients treated for intentional injuries during the study period, 366 were included in the study (32.3%). Of these, 133 (36.3%) subjects were exposed to illicit fentanyl prehospital. There were no demographic differences between cases and controls. Cases had a lower GCS voice score on arrival (median = 4, interquartile range [IQR] = 4-5 versus median = 5, IQR = 4-5, P = 0.02), higher rates of ventilator usage (32.3% versus 21.5%, P = 0.02), and more intensive care unit admissions (27.1% versus 12.0%, P = 0.005). More than half of cases tested negative for opiates (78/133, 58.6%). Cases had more trauma center encounters (26.3% had ≥2 visits versus 15.5%). CONCLUSIONS: Exposure to illicit fentanyl was common among victims of violence in this single-center study. These patients are at increased risk of being admitted to intensive care units and repeated trauma center visits, suggesting fentanyl testing may help identify those who could benefit from violence prevention and substance abuse treatment.

Heroin- and Fentanyl-Induced Respiratory Depression in a Rat Plethysmography Model: Potency, Tolerance, and Sex Differences.

The opioid overdose death toll in the United States is an ongoing public health crisis. We characterized the magnitude and duration of respiratory depression, the leading cause of death in opioid overdose cases, induced by heroin or fentanyl and the development of tolerance in male and female rats. We used whole-body plethysmography to first establish dose-response curves by recording breathing for 60 minutes post-intravenous opioid injection. We then tested the development of respiratory tolerance to acute heroin or fentanyl over several weeks and to chronic fentanyl with acute fentanyl or heroin challenge. Heroin and fentanyl each provoked dose-dependent respiratory depression. Heroin caused prolonged (45-60 minute) respiratory depression in female and male rats, characterized by decreased frequency, tidal volume, and minute ventilation and increased inspiratory time and apneic pause. Fentanyl produced similar changes with a shorter duration (10-15 minutes). High-dose heroin or fentanyl produced robust respiratory depression that was slightly more severe in females and, when given intermittently (acute doses 2 to 3 weeks apart), did not lead to tolerance. In contrast, chronic fentanyl delivered with an osmotic minipump resulted in tolerance to acute fentanyl and heroin, characterized by a shorter duration of respiratory depression. This effect persisted during withdrawal in males only. Our model and experimental design will allow for investigation of the neurobiology of opioid-induced respiratory depression and for testing potential therapeutics to reverse respiratory depression or stimulate breathing. SIGNIFICANCE STATEMENT: Fentanyl was more potent and had shorter duration in producing respiratory depression than heroin in both sexes, whereas female rats were more sensitive than males to heroin-induced respiratory depression. Tolerance/cross-tolerance develops in chronic fentanyl administration but is minimized with long interadministration intervals.

Methamphetamine-Related Mortality in the United States: Co-Involvement of Heroin and Fentanyl, 1999-2021.

Objectives. To examine trends in methamphetamine-related mortality in the United States from 1999 to 2021 and the extent to which these deaths co-involved heroin or fentanyl. Methods. We obtained final and provisional data from the CDC WONDER (Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research) multiple causes of death database for deaths that involved methamphetamine and deaths that involved both methamphetamine and heroin or fentanyl mong US residents aged 15 to 74 years. We plotted the age-adjusted methamphetamine-related mortality rate by year and quantified the proportion of deaths with heroin or fentanyl co-involvement. Finally, we used joinpoint regression to quantify trends in the methamphetamine mortality rate and proportion of deaths with heroin or fentanyl co-involvement. Results. From 1999 to 2021, there was a 50-fold increase in the methamphetamine mortality rate, which was accompanied by an increasing proportion of deaths that co-involved heroin or fentanyl, peaking at 61.2% in 2021. Conclusions. Unprecedented increases in methamphetamine-related mortality have occurred during the last decade, and an increasing proportion of these deaths co-involved heroin or fentanyl. Public Health Implications. Stark increases in methamphetamine-related mortality and heroin or fentanyl co-involvement warrant robust harm reduction efforts, especially for people who engage in polysubstance use. (Am J Public Health. 2023;113(4):416-419. https://doi.org/10.2105/AJPH.2022.307212).

Using Evidence to Inform Legislation Aimed at Curbing Fentanyl Deaths.

This Viewpoint presents an evidence-based argument against criminalization policies and for more treatment-focused policies.

Impact of fentanyl analgesia on the accuracy of HVPG measurements in patients with cirrhosis: a prospective, multicenter study.

BACKGROUND: HVPG measurement is the gold standard for assessing portal hypertension. Many patients decline HVPG measurements due to associated pain. According to previous studies, propofol sedation during HVPG measurements potentially alters HVPG readings. However, opioid analgesics' effects on HVPG await full elucidation. This study aimed to evaluate fentanyl analgesia's effects on HVPG measurement accuracy in patients with cirrhosis. METHODS: This prospective, multicenter study included patients with cirrhosis undergoing HVPG measurements, which were performed preanalgesia and under analgesia with fentanyl injection (1.0 or 1.5 µg/kg). RESULTS: Of the 48 enrolled patients with cirrhosis, 23 were administered 1.0 µg/kg fentanyl analgesia during HVPG measurement. The HVPG was 13.4±4.9 mm Hg in preanalgesia and 13.5±5.2 mm Hg under analgesia. HVPG measurement accuracy was not altered after fentanyl analgesia (p = 0.801). The following measures also did not change: heart rate (p = 0.132), mean arterial pressure (p = 0.348), and blood oxygen saturation (p = 0.748); however, respiratory rate (p = 0.001) changes occurred. The Verbal Numerical Rating Score for comfort under analgesia was higher than that in preanalgesia (p = 0.001). Twenty-five patients were administered 1.5 µg/kg fentanyl analgesia during HVPG measurement. The HVPG was 19.5±5.7 mm Hg in preanalgesia and 19.6±5.6 mm Hg under analgesia. HVPG measurement accuracy did not alter after fentanyl analgesia (p = 0.469). Similarly, the following measures did not change: mean arterial pressure (p = 0.871) and oxygen saturation (p = 0.327); nevertheless, respiratory rate (p = 0.015) and heart rate (p = 0.019) changes occurred. The Verbal Numerical Rating Score for comfort under analgesia was higher than that in preanalgesia (p < 0.001). CONCLUSION: Fentanyl analgesia did not alter HVPG measurement accuracy, and fentanyl improved comfort in patients with cirrhosis during HVPG measurements.

Predicting tolerability of high-dose fentanyl buccal tablets in cancer patients.

BACKGROUND & AIMS: Fentanyl buccal tablets (FBTs) are a rapid-onset opioid indicated for breakthrough cancer pain (BTcP) and FBT titration is needed to optimize BTcP management. We aimed to predict which patients could tolerate a high dose of FBT (400 µg or more at a time). METHODS: A retrospective analysis was performed to assess the final FBT dose. The final FBT doses were compared according to the clinical features. The prediction accuracy of patients tolerant of 400 µg or higher FBT was compared using the area under the receiver operating characteristic (ROC) curves. A risk scoring model based on the odds ratio (OR) was developed from the final multivariable model, and patients were assigned into two groups: low tolerance (0-1 point) and high tolerance (2-3 points). RESULTS: Among 131 patients, the most frequently effective dose of FBT was 200 µg (54%), followed by 100 µg (30%). The median value of morphine equivalent daily doses (MEDD) was 60 mg/day, and the most common daily use was 3-4 times/day. In multivariable analysis, male sex, younger age, and use of FBTs three or more times per day were independently associated with high-dose FBT. According to the risk scoring model, the patients with a final FBT of 400 µg or higher were significantly more in the high tolerance group (17%) compared to the low tolerance group (3%; p = 0.023). CONCLUSIONS: According to the dose relationship between the final FBT dose and the clinical features, three factors (sex, age, daily use of FBT) were independently associated with the final dose of FBT. Our risk score model could help predict tolerance to high-dose FBT and guide the titration plan for BTcP.

A qualitative exploration of unintentional versus intentional exposure to fentanyl among people who use drugs in Austin, TX.

BACKGROUND: The prevalence of deaths involving synthetic opioids has historically been lower in Texas than most U.S. states but more than quadrupled from January 2020 to January 2022. This paper explores the emergence of fentanyl in a drug supply where black tar heroin predominates, a factor considered protective against fentanyl adulteration, through the perspectives of people who use drugs (PWUD). OBJECTIVES: We describe experiences of unintentional exposure to fentanyl, illustrate how some people identify fentanyl in their supply, and present harm reduction strategies that PWUD use to avoid overdose. METHODS: Thirty rapid assessment interviews were conducted in July 2021 at 2 mobile outreach sites of a harm reduction organization in Austin, Texas. The brief semistructured interviews were designed to assess participant fentanyl exposure experiences. RESULTS: Participants were clients who reported using heroin or fentanyl in the past week and had lived in Texas for at least 6 months. Seventeen participants identified as male, 10 as female, and 3 as nonbinary. Half identified as white; other participants were Latinx (6), black (2), American Indian (1), and mixed race (6). Two-thirds were unhoused or in transitional housing. The drug supply in Texas has evolved; most participants reported that the heroin and other drugs they obtained contain fentanyl. Participants detected differences by observing changes in the physical characteristics of the drug, experiencing unexpected effects, and using fentanyl test strips. Many had been unintentionally exposed to fentanyl and expressed concerns about fentanyl's presence. The presence of fentanyl had negative unintended consequences for participants, including adverse effects and developing a dependence on opioids. CONCLUSION: PWUD in Austin, Texas, report increasing prevalence of unintentional fentanyl exposure, despite the predominance of black tar heroin. Pharmacists can provide crucial supplies and education to safeguard the health of this vulnerable population.

Characteristics of xylazine-related deaths in West Virginia-Xylazine-related deaths.

BACKGROUND AND OBJECTIVES: The involvement of xylazine, a veterinary drug, in West Virginia (WV) human drug-related deaths was examined. METHODS: WV drug deaths from 2019 (when xylazine was first identified) to mid-2021. Characteristics including toxicology findings were compared between xylazine and nonxylazine deaths. RESULTS: Of 3292 drug deaths, 117 involved xylazine, and the proportions of deaths with it have increased (1% [2019] to 5% [mid-2021)]. Xylazine decedents had more cointoxicants, with fentanyl (98%) predominant followed by methamphetamine. Xylazine decedents had a significantly greater history of drug or alcohol misuse and hepatic disease. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: In one of the largest analyses of xylazine-involved deaths in a predominantly rural state, identification of xylazine was increasing with multiple cointoxicants (especially fentanyl), and was present in a few deaths with only one other substance involved. Health professionals should be aware of possible enhanced toxicity from xylazine ingestion especially since naloxone does not reverse xylazine's adverse effects.

Fatal fentanyl-associated cerebellitis in a young man.

A 22-year-old man was brought in by EMS for coma and respiratory failure. The initial diagnosis was an opioid overdose but the patient did not respond to naloxone. A head CT revealed findings consistent with cerebellitis. The patient developed obstructive hydrocephalus and herniation. Despite neurosurgical and ICU care, the patient did not recover. Cerebellitis is a seldom-discussed complication of opioid use which may become more common as the opioid and fentanyl epidemic evolves.

Perfil de pacientes grandes consumidores de fentanilo de liberación rápida en un área sanitaria de Córdoba / Profile of patients with abusive consumption of quick-release fentanyl in a health area of Cordoba

Objetivo: Describir el tipo de pacientes que superan la dosis diaria definida (DDD) de fentanilo de liberación inmediata en un área sanitaria.Material y métodos: Estudio observacional, descriptivo, realizado en un área sanitaria de 256.807 habitantes en el que se incluyeron todos los pacientes que superaban la DDD de fentanilo de liberación inmediata en diciembre de 2019.Resultados: Se detectaron 29 pacientes, 58,6% mujeres, con una mediana de edad de 59 (31-87) años, que superaban una media de 3 (1,1-10) veces la DDD de fentanilo de liberación inmediata, en sus distintas presentaciones, siendo la indicación en el 69% de los casos dolor crónico no oncológico (DCNO). La mayoría de los pacientes tomaba benzodiacepinas (79,3%) y el mayor porcentaje de primeras prescripciones de fentanilo de liberación rápida procedía de atención primaria (38%).Conclusiones: En nuestro estudio el uso inadecuado o posible abuso de fentanilo de liberación inmediata se da en mayor proporción en pacientes con DCNO, y en la mayoría de los casos la primera prescripción se realizó en atención primaria. No observamos relación clara con patología psiquiátrica ni otras adicciones. (AU)

Objective: To describe the type of patients that exceed the defined daily dose (DDD) of immediate-release fentanyl in a health area.Material and methods: Observational, descriptive study, carried out in a health area of ​​256,807 inhabitants, which included all patients who passed the immediate-release fentanyl DDD in December 2019.Results: 29 patients were detected, 58.6% female, with a median age of 59 (31-87) years, who exceeded an average of 3 (1.1-10) times the immediate-release fentanyl DDD, in its different presentations, being the indication in 69% of cases chronic non-cancer pain (CNCP). The majority of patients took benzodiazepines (79.3%) and the highest percentage of first-prescriptions for inmediate-release fentanyl came from primary care (38%).Conclusions: In our study, the inappropriate use or possible abuse of immediate-release fentanyl occurs in a greater proportion in patients with CNCP, and in most cases the first prescription was made in primary care. We did not observe a clear relationship with psychiatric pathology or other addictions. (AU)

Intraoperative use of low-dose dexmedetomidine for the prevention of emergence agitation following general anaesthesia in elderly patients: a randomized controlled trial.

OBJECTIVE: To clarify the effect of an intraoperative low-dose dexmedetomidine infusion on emergence agitation following general anaesthesia in elderly patients. METHODS: Eighty elderly patients (> 64-years-old) following elective general anaesthesia for radical cancer surgeries were randomly allocated into two groups (n = 40 each): the dexmedetomidine group (Group D) and the normal saline group (Group C). Anaesthesia was maintained with continuous intravenous infusion of dexmedetomidine at - 0.2 µg kg-1 h-1 in Group D, and an equal volume of normal saline (0.5 ml kg-1 h-1) was given in Group C. All patients were observed for 30 min in the post-anaesthesia care unit (PACU), AFPS and NRS were recorded every 2 min, and the total doses of nalbuphine and fentanyl were calculated in the PACU. MAP and HR were recorded at the time of 10 min (T1), 20 min (T2), 30 min (T3) after dexmedetomidine or saline pumping, and before extubation (T4), immediately after extubation (T5), and 5 min after extubation (T6). We also documented some durations, including anaesthesia duration (D1), surgery duration (D2), duration from the end of surgery to extubation (D3), and emergence agitation duration (D4). RESULTS: The MAP in Group C was significantly higher than that in Group D (P < 0.05), and there were no significant changes between the two groups in HR and MAP within each time point and D1, D2, D3, and D4. The incidence of agitation, NRS score and total dose of nalbuphine and fentanyl were all lower in Group D than in Group C (P < 0.05). CONCLUSION: An intraoperative low-dose dexmedetomidine continuous infusion can reduce emergence agitation following general anaesthesia in elderly patients (> 64-years-old), remain stable in terms of haemodynamics, and not lead to delays in anaesthesia recovery time and extubation time.

Non-fentanyl-derived synthetic opioids emerging during recent years.

PURPOSE: Since the appearance of fentanyl followed by its many kinds of analogues around 1988, North America has been exposed to fierce synthetic opioid pandemic resulting in more than 130,000 deaths due to their overdoses until May 2019, when China declared to prohibit the licit fentanyl analog production. However, the Chinese announcement did not go into force in USA due to the adroit strategies of tough traffickers. Thus, contrary to the expectation, the number of synthetic opioid products and their poisoning cases in USA has increased by about 30%; especially, various benzimidazole synthetic opioids have revived on the illicit drug market during a recent few years. In this article, the recent abrupt changes in the situations of illicit synthetic opioid market and their current abuses are described. METHODS: Various databases, such as SciFinder, Google, and Google Scholar, were utilized to collect relevant reports referring old but newly appearing synthetic opioids. RESULTS: At the present time, there are several families of new synthetic opioids, which are not fentanyl derivatives; MT-45 and its analogs, benzamide and 2-phenylacetamide opioids (U-series opioids), and benzimidazole opioids. Most of the above substances had been developed in 1950s to 1970s, but had never been used as analgesic medicines, because of their severe adverse effects, such as respiratory depression, physical dependence, and resulting deaths. However, there is possibility that these drugs will become main illicit synthetic opioids in place of the fentanyl analogs during coming several years from this time. CONCLUSIONS: All of the above non-fentanyl-derived families had been developed 50-70 years ago to establish them as analgesic medicines, but had been unsuccessful. These drugs largely appeared in the illicit drug markets in North America, Europe, and Australia, during recent years. Pharmacological, toxicological, and metabolic studies are insufficient for benzamide and 2-phenylacetamide opioids, and are very scant especially for benzimidazole opioids. This time we should start studying pharmacotoxicology of the newly emerging synthetic opioids to alert forensic toxicologists in the world and to suppress their rapid and wide spread in the world.