“Tranq-dope” overdose and mortality: lethality induced by fentanyl and xylazine
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PROVIDER: S-EPMC10637371 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:The recreational use of fentanyl in combination with xylazine (i.e., "tranq-dope") represents a rapidly emerging public health threat characterized by significant toxicity and mortality. This study quantified the interactions between these drugs on lethality and examined the effectiveness of potential rescue medications to prevent a lethal overdose. Male and female mice were administered acute doses of fentanyl, xylazine, or their combination via intraperitoneal injection, and lethality was determined 30, 60, 90, 120, and 1440 min (24 hr) after administration. Both fentanyl and xylazine produced dose-dependent increases in lethality when administered alone. A nonlethal dose of fentanyl (56 mg/kg) produced an approximately 5-fold decrease in the estimated LD50 for xylazine (i.e., the dose estimated to produce lethality in 50% of the population). Notably, a nonlethal dose of xylazine (100 mg/kg) produced an approximately 100-fold decrease in the estimated LD50 for fentanyl. The opioid receptor antagonist, naloxone (3 mg/kg), but not the alpha-2 adrenergic receptor antagonist, yohimbine (3 mg/kg), significantly decreased the lethality of a fentanyl-xylazine combination. Lethality was rapid, with death occurring within 10 min after a high dose combination and generally within 30 min at lower dose combinations. Males were more sensitive to the lethal effects of fentanyl-xylazine combinations under some conditions, suggesting biologically relevant sex differences in sensitivity to fentanyl-xylazine lethality. These data provide the first quantification of the lethal effects of "tranq-dope" and suggest that rapid administration of naloxone may be effective at preventing death following overdose.
| S-EPMC10557575 | biostudies-literature
Project description:Fatal opioid overdoses in the United States have nearly tripled during the past decade, with greater than 92% involving a synthetic opioid like fentanyl. Fentanyl potently activates the μ-opioid receptor to induce both analgesia and respiratory depression. The danger of illicit fentanyl has recently been exacerbated by adulteration with xylazine, an α2-adrenergic receptor agonist typically used as a veterinary anesthetic. In 2023, over a 1,000% increase in xylazine-positive overdoses was reported in some regions of the U.S. Xylazine has been shown to potentiate the lethality of fentanyl in mice, yet a mechanistic underpinning for this effect has not been defined. Herein, we evaluate fentanyl, xylazine, and their combination in whole-body plethysmography (to measure respiration) and pulse oximetry (to measure blood oxygen saturation and heart rate) in male and female CD-1 mice. We show that xylazine decreases breathing rate more than fentanyl by increasing the expiration time. In contrast, fentanyl primarily reduces breathing by inhibiting inspiration, and xylazine exacerbates these effects. Fentanyl but not xylazine decreased blood oxygen saturation, and when combined, xylazine did not change the maximum level of fentanyl-induced hypoxia. Xylazine also reduced heart rate more than fentanyl. Finally, loss in blood oxygen saturation correlated with the frequency of fentanyl-induced apneas, but not breathing rate. Together, these findings provide insight into how the addition of xylazine to illicit fentanyl may increase the risk of overdose.
| S-EPMC11370410 | biostudies-literature
Project description: Not available
| S-EPMC11563672 | biostudies-literature
Project description:BackgroundAs of July 2018, 45 United States (US) states and the District of Columbia have enacted an overdose Good Samaritan law (GSL). These laws, which provide limited criminal immunity to individuals who request assistance during an overdose, may be of importance in the current wave of the overdose epidemic, which is driven primarily by illicit opioids including heroin and fentanyl. There are substantial differences in the structures of states' GSL laws which may impact their effectiveness. This study compared GSLs which have legal provisions protecting from arrest and laws which have more limited protections.MethodsUsing national county-level overdose mortality data from 3109 US counties, we examined the association of enactment of GSLs with protection from arrest and GSLs with more limited protections with subsequent overdose mortality between 2013 and 2018. Since GSLs are often enacted in conjunction with Naloxone Access Laws (NAL), we examined the effect of GSLs separately and in conjunction with NAL. We conducted these analyses using hierarchical Bayesian spatiotemporal Poisson models.ResultsGSLs with protections against arrest enactment in conjunction with a NAL were associated with 7% lower rates of all overdose deaths (rate ratio (RR): 0.93% Credible Interval (CI): 0.89-0.97), 10% lower rates in opioid overdose deaths (RR: 0.90; CI: 0.85-0.95) and 11% lower rates of heroin/synthetic overdose mortality (RR: 0.89; CI: 0.82-0.96) two years after enactment, compared to rates in states without these laws. Significant reductions in overdose mortality were not seen for GSLs with protections for charge or prosecution.ConclusionGSLs with more expansive legal protections combined with a NAL, were associated with lower rates of overdose deaths, although these risk reductions take time to manifest. Policy makers should consider enacting and implementing more expansive GSLs with arrest protections to increase the likelihood people will contact emergency services in the event of an overdose.
| S-EPMC9529169 | biostudies-literature
Project description:Illicitly-manufactured fentanyl and stimulants have replaced prescription opioids as the primary contributors to fatal overdoses in the United States (US), yet the street supply of these substances is challenging to quantify. Building on the foundation of prior research on law enforcement drug reports, the present study compares publicly available forensic laboratory drug report measures to identify which measures account for the most variation in drug overdose mortality between states, within states over time, and in various demographic groups. Drug reports from the National Forensic Laboratory Information System and drug overdose mortality rates from the Centers for Disease Control and Prevention were examined for all US states and the District of Columbia, 2013-2021 (459 state-years). State- and year- fixed effects models regressed drug overdose mortality rates (in the overall population and subpopulations by sex, age, and race/ethnicity) on various drug report measures, including rates per population and proportional shares of drug reports positive for fentanyl/fentanyl-related compounds, heroin, cocaine, methamphetamine, and xylazine. For drug overdose death rates in the overall population and nearly all subpopulations examined by sex, race/ethnicity, and age, the model including all drug report proportional measures represented the best-performing model (as identified via the lowest Akaike Information Criterion and highest within R-squared value), followed by the model including only the fentanyl/fentanyl-related compounds proportion. Findings support the utility of publicly available drug report composition measures, particularly the proportion of fentanyl/fentanyl-related compounds, as predictors of drug overdose mortality in the US and in various subpopulations.
| S-EPMC10641574 | biostudies-literature
Project description: Not available
| S-EPMC10388669 | biostudies-literature
Project description:BackgroundUnited States drug overdose deaths are being driven by the increasing prevalence of fentanyl, but whether patients are knowingly using fentanyl is unclear. We examined the analytical confirmation of fentanyl in emergency department (ED) patients with documented heroin overdose.HypothesisWe hypothesized that the proportion of fentanyl and fentanyl analogs would be higher than that of confirmed heroin.MethodsThis is a subgroup analysis from a prospective multicenter consecutive cohort of ED patients age 18+ with opioid overdose presenting to 10 US sites within the Toxicology Investigators Consortium from 2020 to 2021. Toxicology analysis was performed using liquid chromatography quadrupole time-of-flight mass spectrometry. De-identified toxicology results were paired with the clinical database. The primary outcome was the proportion of patients with fentanyl analytes detected in their serum.ResultsOf 1006 patients screened, 406 were eligible, and of 168 patients who reported that they had taken heroin or had a documented heroin overdose, 88% (n = 147) were in fact found to have fentanyl and/or a fentanyl analog present on serum analysis (p < 0.0001). In contrast, only 46 of the 168 patients with reported or documented heroin overdose (27%) were found to have heroin biomarkers present.ConclusionThe prevalence of confirmed fentanyl in ED patients with suspected heroin overdose was extremely high, while the prevalence of heroin was very low. There was a high degree of mismatch between the opioids believed to be the overdose agent versus the actual opioids identified on serum toxicology. Clinicians in the United States should presume that fentanyl is involved in all illicit opioid overdoses and should counsel patients on harm reduction measures.
| S-EPMC11331419 | biostudies-literature
Project description:BackgroundDrug overdose mortality continues to increase, now driven by fentanyl. Prevention tools such as naloxone and medications to treat opioid use disorder are not sufficient to control overdose rates; additional strategies are urgently needed.ObjectiveWe sought to adapt a behavioral intervention to prevent opioid overdose (repeated-dose behavioral intervention to reduce opioid overdose [REBOOT]) that had been successfully piloted in San Francisco, California, United States, to the setting of Boston, Massachusetts, United States, and the era of fentanyl for a full efficacy trial.MethodsWe used the assessment, decision, adaptation, production, topical experts, integration, training, and testing (ADAPT-ITT) framework for intervention adaptation. We first identified opioid overdose survivors who were actively using opioids as the population of interest and REBOOT as the intervention to be adapted. We then performed theater testing and elicited feedback with 2 focus groups (n=10) in Boston in 2018. All participants had used opioids that were not prescribed to them in the past year and experienced an opioid overdose during their lifetime. We incorporated focus group findings into our initial draft of the adapted REBOOT intervention. The adapted intervention was reviewed by 3 topical experts, and their feedback was integrated into a subsequent draft. We trained study staff on the intervention and made final refinements based on internal piloting. This paper describes the overall ADAPT-ITT process for intervention adaptation, as well as a qualitative analysis of the focus groups. Working independently, 2 authors (VMM and JA) reviewed the focus group transcripts and coded them for salient and common themes using the constant comparison method, meeting to discuss any discrepancies until consensus was reached. Codes and themes were then mapped onto the REBOOT counseling steps.ResultsFocus group findings contributed to substantial changes in the counseling intervention to better address fentanyl overdose risk. Participants described the widespread prevalence of fentanyl and said that, although they tried to avoid it, avoidance was becoming impossible. Using alone and lower opioid tolerance were identified as contributors to overdose risk. Slow shots or tester shots were acceptable and considered effective to reduce risk. Naloxone was considered an effective reversal strategy. Although calling emergency services was not ruled out, participants described techniques to prevent the arrival of police on the scene. Expert review and internal piloting improved the intervention manual through increased participant centeredness, clarity, and usability.ConclusionsWe successfully completed the ADAPT-ITT approach for an overdose prevention intervention, using theater testing with people who use opioids to incorporate the perspectives of people who use drugs into a substance use intervention. In the current crisis, overdose prevention strategies must be adapted to the context of fentanyl, and innovative strategies must be deployed, including behavioral interventions.Trial registrationClinicalTrials.gov NCT03838510; https://clinicaltrials.gov/ct2/show/NCT03838510.
| S-EPMC9494212 | biostudies-literature
Project description:ImportanceXylazine is increasingly reported in street drugs and fatal overdoses in the US, yet state-level data are limited, hampering local public health responses.ObjectiveTo gather available state-level data on xylazine involvement in overdose deaths and in forensic drug reports.Design, setting, and participantsThis cross-sectional study was a secondary analysis of 2019 to 2022 data from the National Forensic Laboratory Information System (NFLIS), National Center for Health Statistics, and individual states' medical examiner or public health agency reports. Data were analyzed from August to October 2023.ExposureState.Main outcomes and measuresYearly xylazine-related overdose deaths per 100 000 residents; xylazine NFLIS drug reports, both per 100 000 residents and as a percentage of all NFLIS drug reports (from samples of drugs seized by law enforcement and analyzed by NFLIS-participating laboratories).ResultsA total of 63 state-years were included in analyses of mortality rates, while 204 state-years were included in analyses of NFLIS reports. According to the publicly available data compiled in this study, at least 43 states reported at least 1 xylazine-related overdose death from 2019 to 2022, yet yearly totals of xylazine-related deaths were available for only 21 states. Of states with data available, xylazine-involved overdose death rates were highest in Vermont (10.5 per 100 000 residents) and Connecticut (9.8 per 100 000 residents) in 2022. In 2019, 16 states had zero xylazine reports included in NFLIS reports; in 2022, only 2 states had zero xylazine reports and all but 3 states had recorded an increase in xylazine's representation in NFLIS reports. In 2022, xylazine represented 16.17% of all NFLIS reports in Delaware and between 5.95% and 7.00% of NFLIS reports in Connecticut, Maryland, District of Columbia, New Jersey, and Rhode Island, yet less than 1.0% of NFLIS reports in 35 different states.Conclusions and relevanceIn this cross-sectional study of publicly available data on fatal overdoses and drugs analyzed by forensic laboratories, xylazine's reported presence in overdose deaths and forensic reports was concentrated in the eastern US yet extended across the country to encompass nearly all states. In spite of xylazine's geographic reach, yearly state-level numbers of xylazine-related overdose deaths were publicly available for less than half of all states.
| S-EPMC10770774 | biostudies-literature
Project description:The opioid crisis in the United States is primarily driven by the highly potent synthetic opioid fentanyl leading to >70,000 overdose deaths annually; thus, new therapies for fentanyl overdose are urgently needed. Here, we present the first clinic-ready, fully human monoclonal antibody CSX-1004 with picomolar affinity for fentanyl and related analogs. In mice CSX-1004 reverses fentanyl antinociception and the intractable respiratory depression caused by the ultrapotent opioid carfentanil. Moreover, toxicokinetic evaluation in a repeat-dose rat study and human tissue cross-reactivity study reveals a favorable pharmacokinetic profile of CSX-1004 with no safety-related issues. Using a highly translational non-human primate (NHP) model of respiratory depression, we demonstrate CSX-1004-mediated protection from repeated fentanyl challenges for 3-4 weeks. Furthermore, treatment with CSX-1004 produces up to a 15-fold potency reduction of fentanyl in NHP respiration, antinociception and operant responding assays without affecting non-fentanyl opioids like oxycodone. Taken together, our data establish the feasibility of CSX-1004 as a promising candidate medication for preventing and reversing fentanyl-induced overdose.
| S-EPMC10698161 | biostudies-literature