Illicitly Manufactured Fentanyl Research Articles

A Quantitative LC-MS/MS Method for Xylazine and Metabolites in Urine

Abstract The prevalence of xylazine in fatal overdoses is on the rise across the United States, as reported by the Center for Disease Control and Prevention (CDC). Xylazine, a nonopioid sedative commonly used to adulterate illicitly manufactured fentanyl (IMF), poses severe health risks, including soft tissue wounds and increased overdose potential. Originally emerging in the eastern United States, its presence became widespread in Philadelphia overdose cases by 2019. Recently, there has been a notable increase in xylazine infiltrating the drug supply on the West Coast, as evidenced by a surveillance program in San Francisco in June and July 2023. Existing literature quantifying xylazine concentrations in human urine faces limitations due to the high variability in the drug supply regionally and temporally, hindering generalizability to West Coast patients. To address this gap, we developed and validated a quantitative LC-MS/MS method following Scientific Working Group for Forensic Toxicology (SWGTOX) guidelines to establish baseline urine concentrations in West Coast patients. The primary objective of this study was to develop a quantitative method for analyzing xylazine and two metabolites in the urine of exposed patients to establish expected concentrations. Chromatographic separation utilized a Shimadzu Prominence LC-20 series liquid chromatography system and a Phenomenex C-18 2.3µm 100 Å 50x3mm Kinetex column. Data acquisition employed a Sciex Triple Quad 4500. Mobile phases included Honeywell Water LC-MS grade and Honeywell Acetonitrile LC-MS grade. Xylazine and metabolites were detected using multiple reaction monitoring with the following transitions: xylazine 221.1/164.1 and 221.1/90.0,4-hydroxy-xylazine 237.1/137.1 and 231.1/136.1,2,6-dimethylaniline 121.9/105.1 and 121.9/77.0. Validation followed SWGTOX guidelines, and de-identified urine samples (n = 46) from the San Francisco Opiate Treatment Outpatient Program were analyzed.The method was linear from 1 to 10,000 ng/ml, established through triplicate analyses over five days, with an R2 value of 0.9972. The lower limit of quantification for xylazine was determined to be 1 ng/ml, with a coefficient of variation (CV) of 10.01% across 20 samples. Intra-day and inter-day precision was assessed using three different spiked pools representing low, medium, and high values, yielding CV values of 8.71%,7.45%, and 5.99%, respectively for inter-day precision. The intra-day CV ranged from 0.14% to 11.86%,0.82%to 5.37%, and 0.92% to 7.05% over the course of five days. In patients, the concentration of xylazine ranged from 4 to 3,789 ng/ml, with only one patient sample showing the presence of the metabolite 4-hydroxy-xylazine, while there was no detection of 2,6-dimethylaniline in this sample set. The LC-MS/MS method, validated according to SWGTOX guidelines, is suitable for quantifying xylazine in urine samples. This study, the largest on West Coast patients to date, provides essential baseline information for local clinicians dealing with the health implications of xylazine exposure, expanding knowledge beyond the East Coast-focused literature.

Fentanyl, Heroin, Methamphetamine, and Cocaine Analyte Concentrations in Urine Drug Testing Specimens

The US is experiencing a protracted drug overdose crisis primarily associated with exposure to illicitly manufactured fentanyl (IMF), methamphetamine, and cocaine. Overdose risk and treatment responses may be directly affected by absolute drug exposure concentrations and drug use prevalence. To quantify changes in absolute drug exposure concentrations from 2013 to 2023. This cross-sectional study analyzed urine drug testing (UDT) results from urine specimens collected between January 1, 2013, and August 22, 2023, in 49 states and the District of Columbia. Urine specimens were obtained from patients aged 18 years or older who presented to substance use disorder treatment clinics. The UDT was ordered by clinicians based on medical necessity. Urine specimens were analyzed for the following drugs or metabolites (analytes tested in parentheses): fentanyl (fentanyl), heroin (6-monoacetylmorphine), cocaine (benzoylecgonine), and methamphetamine (methamphetamine) using liquid chromatography with tandem mass spectrometry. Relative concentrations of fentanyl, heroin, cocaine, and methamphetamine. Creatinine-normalized drug concentration values were log-transformed prior to visualization and statistical analyses. The Mann-Kendall trend test was performed to examine trends over time. To estimate the geospatial and temporal patterns of drug concentration, a second series of models (1 for each drug) with an interaction effect for clinic location and collection year were fit. A total of 921 931 unique UDT samples were collected from patients (549 042 males [59.6%]; median [IQR] age, 34 [27-44] years). The adjusted fentanyl concentration in urine specimens was 38.23 (95% CI, 35.93-40.67) ng/mg creatinine in 2023 and 4.61 (95% CI, 3.59-5.91) ng/mg creatinine in 2013. The adjusted methamphetamine concentration was 3461.59 (95% CI, 3271.88-3662.30) ng/mg creatinine in 2023 and 665.27 (95% CI, 608.51-727.32) ng/mg creatinine in 2013. The adjusted cocaine concentration was 1122.23 (95% CI, 1032.41-1219.87) ng/mg creatinine in 2023 and 559.71 (95% CI, 524.69-597.06) ng/mg creatinine in 2013. The adjusted heroin concentration was 58.36 (95% CI, 48.26-70.58) ng/mg creatinine in 2023 and 146.59 (95% CI, 136.06-157.92) ng/mg creatinine in 2013. Drug concentrations varied across US Census divisions. This cross-sectional study found that absolute concentrations of fentanyl, methamphetamine, and cocaine in urine specimens increased from 2013 to 2023, with a decrease in heroin concentration during that period. The findings suggest that exposure to these substances, as well as the illicit drug supply, has fundamentally changed in many parts of the US, highlighting the need to reinforce surveillance initiatives and accelerate efforts to treat individuals with IMF and/or stimulant exposure.

Exploring the Psychological Side of Fentanyl: A Scoping Review to Disclose the Psychosocial Dimensions of Illicitly Manufactured Fentanyl Users

Background Fentanyl is a powerful opioid. The abuse and overdoses related to Illicitly Manufactured Fentanyl (IMF) have become more prevalent. The majority of clinical studies on fentanyl have focused on its medical and biological aspects, particularly its addictive properties. Few studies have delved into the psychological aspects of illicit fentanyl use, and there is currently no comprehensive review providing a structured psycho-social profile of the population groups most vulnerable to its effects. The goal of this Scoping Review was to construct a psychological and social profile of individuals at risk of using illicit fentanyl. This profile will serve as a guiding force for shaping behavioral policies and public health prevention efforts necessary to face the recent pandemic. Methods Following the PRISMA guidelines we conducted a Scoping Review focused on the following research question: What are the practical psycho-social implications of illicit fentanyl use in the global population? Results The bibliographic research was carried out in the databases of Medline, Scopus, and PsycNet. The articles resulting from the research phase in the databases listed above produced a total of 17737 reports. After the screening process, 10 studies were included in the scoping review. Discussion and Conclusion This scoping review was the first to consistently and systematically outline the psychosocial implications of fentanyl dependence. Users of IMF are consistently younger than other drug users. People using fentanyl have a relatively low perception of risk. On the psycho-social levels, there is a significant correlation between fentanyl use and mental disorders such as suicidal thoughts, anxiety disorders, and depression. The development of psychotherapy, along with digital tools such as apps and online platforms, can be an initial step in addressing this challenge.

Self-Reported Illicitly Manufactured Fentanyl Use and Associated Health and Substance Use Risks in the United States, 2022

Objective Illicitly manufactured fentanyl (IMF) has emerged as a catalyst of the recent drug epidemic in the United States. To devise more targeted and effective prevention and treatment strategies, it is crucial to understand the demographics of the population who consumes IMF and their health and associated substance use risks. Therefore, this study explores the sociodemographic characteristics, health diagnoses, and drug injection practices of individuals reporting IMF use. Methods Data were derived from the 2022 National Survey on Drug Use Health, based on a nationally representative sample of non-institutionalized individuals aged 12 and older in the United States. Focusing on 306 adults who reported ever using IMF, we examined their sociodemographic characteristics, health diagnoses, and substance-related behaviors in comparison to adults with a drug use disorder who did not report IMF use, using logistic regression analyses. Results The majority of U.S. adults reporting IMF use were aged 35–64, male, non-Hispanic White, with a high school education or lower, never married, and had an annual household income below $40,000. Compared to adults with a drug use disorder who did not report IMF use, they were more likely to report heart conditions (AOR = 2.67, 95% CI = 1.29–5.54) and Hepatitis B or C (AOR = 8.35, 95% CI = 4.05–17.02). Nearly half of this group had an opioid use disorder (OUD) in the past year, and 65.7% (95% CI = 56.7–74.8) reported a history of injecting drugs. Conclusions To effectively curb the current drug epidemic, incorporating effective treatment for OUD and harm reduction strategies is crucial.

Illicit Fentanyl Use and Hepatitis C Virus Seroconversion Among People Who Inject Drugs in Tijuana and San Diego: Results From a Binational Cohort Study.

Illicitly manufactured fentanyl (IMF) increases overdose mortality, but its role in infectious disease transmission is unknown. We examined whether IMF use predicts hepatitis C virus (HCV) and human immunodeficiency virus (HIV) incidence among a cohort of people who inject drugs (PWID) in San Diego, California and Tijuana, Mexico. PWID were recruited during 2020-2022, undergoing semi-annual interviewer-administered surveys and HIV and HCV serological rapid tests through 2024. Cox regression was conducted to examine predictors of seroconversion considering self-reported IMF use as a 6-month lagged, time-dependent covariate. Of 398 PWID at baseline, 67% resided in San Diego, 70% were male, median age was 43 years, 42% reported receptive needle sharing, and 25% reported using IMF. HCV incidence was 14.26 per 100 person-years (95% confidence interval [CI]: 11.49-17.02), and HIV incidence was 1.29 (95% CI: .49-2.10). IMF was associated with HCV seroconversion, with a univariable hazard ratio (HR) of 1.64 (95% CI: 1.09-2.40), and multivariable HR of 1.57 (95% CI: 1.03-2.40). The direction of the relationship with HIV was similar, albeit not significant (HR 2.39; 95% CI: .66-8.64). We document a novel association between IMF and HCV seroconversion among PWID in Tijuana-San Diego. Few HIV seroconversions (n = 10) precluded our ability to assess if a similar relationship held for HIV. IMF's short half-life may destabilize PWID-increasing the need for repeat dosing and sharing smoking materials and syringes. New preventive care approaches may reduce HCV transmission in the fentanyl era.

Managing Opioid Withdrawal Symptoms During the Fentanyl Crisis: A Review.

Illicitly manufactured fentanyl (IMF) is a significant contributor to the increasing rates of overdose-related deaths. Its high potency and lipophilicity can complicate opioid withdrawal syndromes (OWS) and the subsequent management of opioid use disorder (OUD). This scoping review aimed to collate the current OWS management of study populations seeking treatment for OWS and/or OUD directly from an unregulated opioid supply, such as IMF. Therefore, the focus was on therapeutic interventions published between January 2010 and November 2023, overlapping with the period of increasing IMF exposure. A health science librarian conducted a systematic search on November 13, 2023. A total of 426 studies were screened, and 173 studies were reviewed at the full-text level. Forty-nine studies met the inclusion criteria. Buprenorphine and naltrexone were included in most studies with the goal of transitioning to a long-acting injectable version. Various augmenting agents were tested (buspirone, memantine, suvorexant, gabapentin, and pregabalin); however, the liberal use of adjunctive medication and shortened timelines to initiation had the most consistently positive results. Outside of FDA-approved medications for OUD, lofexidine, gabapentin, and suvorexant have limited evidence for augmenting opioid agonist initiation. Trials often have low retention rates, particularly when opioid agonist washout is required. Neurostimulation strategies were promising; however, they were developed and studied early. Precipitated withdrawal is a concern; however, the rates were low and adequately mitigated or managed with low- or high-dose buprenorphine induction. Maintenance treatment continues to be superior to detoxification without continued management. Shorter induction protocols allow patients to initiate evidence-based treatment more quickly, reducing the use of illicit or non-prescribed substances.

Illicitly Manufactured Fentanyl Use Among Individuals in the U.S., 2022

IntroductionWhile morbidity and mortality related to synthetic opioids such as illicitly manufactured fentanyl (IMF) are monitored in the U.S., there has been a lack of national survey data focusing on use. Survey data are important as self-report can help estimate prevalence of use among living persons. MethodsData were examined from the 2022 National Survey on Drug Use and Health, a nationally representative probability sample of noninstitutionalized individuals age ≥12 in the U.S. (N=59,069). Prevalence and correlates of past-year use of IMF were estimated. Data were analyzed in 2024. ResultsThe estimated prevalence of past-year IMF use was 0.23% (95% confidence interval [CI]: 0.17-0.31). Compared to no past-year use, individuals were at increased odds for IMF use if proxy-diagnosed with use disorder involving use of cannabis (aOR=3.72, 95% CI: 1.34-10.32), cocaine (aOR=11.96, 95% CI: 4.78-29.93), methamphetamine (aOR=5.60, 95% CI: 1.65-19.02), heroin (aOR=20.56, 95% CI: 8.90-47.52), and/or prescription opioids (aOR=10.65, 95% CI: 3.54-32.03). (Mis)use without use disorder was only significant for prescription opioids (aOR=5.77, 95% CI: 2.55-13.06). Those receiving treatment for substance use in the past year were also at increased odds for use (aOR=5.79, 95% CI: 2.58-13.00). ConclusionsPrevalence of IMF use is rare in the general U.S. population. While past-year (mis)use of other drugs (without use disorder) was not consistently associated with IMF use, cannabis, cocaine, methamphetamine, heroin, and prescription opioid use disorder was associated with higher odds of IMF use, suggesting that more “severe” use of various drugs is more of a risk factor than use.

Opioid crisis in the USA: what are implications for Switzerland?

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.

Characteristics of Overdose Deaths Related to Illicitly Manufactured Fentanyl – Arizona, July 2019 – June 2020

ABSTRACT Using the Arizona State Unintentional Drug Overdose Reporting System (AZ-SUDORS), the study aims to identify the social and drug characteristics of illicitly manufactured fentanyl (IMF)-related overdose deaths. The data include drug overdose deaths from July 1, 2019 to June 30, 2020. Decedents were categorized into four groups by types of opioids detected: (1) IMF-positive; (2) heroin-positive (negative for IMF); (3) pharmaceutical opioid-positive (negative for heroin or IMF); (4) nonopioid. Bivariate statistics were used to compare differences between IMF and other groups. Among 2,029 decedents, 77.8% tested positive for opioids. The IMF group included 57.9%, the heroin group included 9.5%, the pharmaceutical opioid group 10.5%, and the nonopioid group 22.2%. The IMF group was younger (mean age 35.0), more likely to be from a large urban area (78.2%), and with a greater proportion of ethnic/racial minorities (48.6%), compared to the other three groups. The IMF group was less likely to test positive for methamphetamine (24.9%), compared to heroin (63.7%) or pharmaceutical opioid groups (34.0%), but more likely to test positive for cannabis (31.3%), compared to the other three groups. Our data show disproportionate IMF impacts on younger persons and ethnic minorities. Interventions need to be tailored to account for distinct psychosocial profiles associated with IMF use.

B-327 Evidence of Missed Novel Psychoactive Substances (NPS) in Unexpected Fentanyl Positives

Abstract Background Recent data published by the CDC indicated that overdose deaths in the United States began to increase significantly in 2020 and continued throughout 2021. Synthetic opioids, such as illicitly-manufactured fentanyl (IMF), have been a primary driver in overdose deaths. There has been a concomitant increase in both the prevalence and diversification of novel psychoactive substances (NPS) and IMF. We performed a blinded secondary analysis of remnant samples to further characterize the incidence in which individuals are encountering NPS when using non-prescribed fentanyl. Various classes of NPS compounds (e.g., designer opioids, designer benzodiazepines, xylazine) were evaluated in samples that were originally positive for fentanyl but did not include a request from the provider for NPS testing to be performed. Methods This study was IRB approved. A sampling of 200 urine or oral fluid specimens collected from individuals as part of their routine medical treatment, wherein definitive testing for fentanyl and norfentanyl was performed and the drug and metabolite were both identified above the upper limit of quantitation of the assay, underwent additional analysis for NPS. Samples were excluded from blinded secondary analysis if any NPS testing, regardless of drug class, was originally ordered and performed. Additional testing that was performed included the following classes of drugs: designer opioids, designer benzodiazepines, synthetic cannabinoids, synthetic stimulants, hallucinogens/dissociatives, xylazine, tianeptine, and phenibut. Results Specimens within the sample set (N: 200) that were originally positive for fentanyl without a previous request for NPS testing originated from 30 different states within the US. These samples were originally collected between 9/19/2022–1/12/2023. Of those that underwent additional analysis after initial reporting of positive fentanyl results, 117 (58.5%) had at least one analyte within an NPS class identified. Designer opioids (N: 93, 47%), and xylazine (N: 76, 38%), followed by designer benzodiazepines (N: 16, 8%), synthetic stimulants (N: 4, 2%), and hallucinogens/dissociatives (N:3, 2%) were the most frequent compounds detected on a per sample basis. No synthetic cannabinoids were detected within this sample set. Conclusion Although much of the national focus around fatal and non-fatal overdoses centers on intentional and unintentional exposures to IMF, healthcare providers and the general public must be made aware of the prevalence of NPS. These compounds, which are often intentionally added to drugs sold as fentanyl to enhance the drug potency, can increase risk for an adverse event. Of paramount importance is that the effects of substances such as xylazine and designer benzodiazepines, which contribute to central nervous system depression, are not effectively reversed by administration of naloxone, a mainstay of harm reduction protocols. Knowledge of the prevalence of these compounds should impact clinical decision-making and individual risk mitigation plans. From a broader perspective, improving understanding of the incidence in which these drugs are found within communities could improve overall surveillance efforts on current drug use trends.

Attitudes and experiences with fentanyl contamination of methamphetamine: exploring self-reports and urine toxicology among persons who use methamphetamine and other drugs

BackgroundThere are growing concerns about illicitly manufactured fentanyl (IMF) contamination of methamphetamine. This study aims to characterize the lay views and experiences with IMF-contaminated methamphetamine (IMF/meth) and identify participants with unknown IMF exposures through urine toxicology analysis.MethodsBetween December-2019 and November-2021, structured interviews were conducted with 91 individuals who reported past 30-day use of methamphetamine and resided in Dayton, Ohio, USA. Lab-based urine toxicology analyses were conducted to identify fentanyl/analogs, methamphetamine, and other drugs. Bivariate analyses were conducted to identify characteristics associated with attitudes and experiences with IMF/meth, and unknown IMF exposures.ResultsThe majority (95.6%) of the study participants were non-Hispanic white, and 52.7% were female. Past 30-day use of methamphetamine was reported on a mean of 18.7 (SD 9.1) days, and 62.6% also reported past 30-day use of heroin/IMF. Most (76.9%) had a history of an unintentional drug-related overdose, but 38.5% rated their current risk for an opioid overdose as none. Besides fentanyl (71.9%), toxicology analysis identified nine fentanyl analogs/metabolites (e.g., 42.7% acetyl fentanyl, 19.0% fluorofentanyl, 5.6% carfentanil), and 12.4% tested positive for Xylazine. The majority (71.4%) believed that IMF/meth was common, and 59.3% reported prior exposures to IMF/meth. 11.2% tested positive for IMF but reported no past 30-day heroin/IMF use (unknown exposure to IMF). Views that IMF/meth was common showed association with homelessness (p = 0.04), prior overdose (p = 0.028), and greater perceived risk of opioid overdose (p = 0.019). Self-reported exposure to IMF/meth was associated with homelessness (p = 0.007) and obtaining take-home naloxone (p = 0.025). Individuals with unknown IMF exposure (test positive for IMF, no reported past 30-day heroin/IMF use) were older (49.9 vs. 41.1 years, p < 0.01), and reported more frequent past 30-day use of methamphetamine (24.4 vs. 18.0 days, p < 0.05). They indicated lower perceived risk of opioid overdose (0.1 vs. 1.9, scale from 0 = “none” to 4 = “high,” p < 0.001).DiscussionThis study suggests a need for targeted interventions for people who use methamphetamine and expansion of drug checking and other harm reduction services.

Association between law enforcement seizures of illicit drugs and drug overdose deaths involving cocaine and methamphetamine, Ohio, 2014–2019

BackgroundThe United States continues to experience a crisis of mounting opioid overdose deaths involving cocaine and methamphetamine (hereafter illicit stimulants). Law enforcement drug seizure data present a unique opportunity to examine the association between illicit-stimulant-involved overdose deaths (ISODs) and the illicit drug supply. Our objective is to better understand correlations between illicit drug market trends and increases in ISODs in Ohio in 2014–2019. MethodsThis observational study analyzes the universe of ISODs and drug seizures in Ohio from 2014 to 2019. We use graphs and descriptive statistics to characterize trends over time and estimate a time series model of their association. ISODs were summed to yield monthly statewide counts of seizures containing methamphetamine, cocaine, illicitly manufactured fentanyl (IMF), and other non-IMF opioids (e.g., heroin). All rates were calculated per 100,000 persons. ResultsRoughly 80% of ISODs in Ohio from 2014 to 2019 involved an opioid, with IMF co-occurring in 90% of ISODs by 2019. Methamphetamine and cocaine seizures containing IMF were associated with 0.439 (p < .01) and 0.457 (p < .01) additional deaths per 100,000 persons per month, respectively. IMF seizures not containing cocaine nor methamphetamine were also associated with additional ISODs (0.119, p < .01) and seizures of illicit stimulants not containing IMF were not associated with ISODs. ConclusionsThe number of ISODs was extremely high when IMF was co-involved and relatively low without IMF involvement. By demonstrating how supply-side trends correspond with ISOD rates, the current study bolsters the analytical utility of law enforcement seizures and complements growing literature in the field.

Simulating the impact of Addiction Consult Services in the context of drug supply contamination, hospitalizations, and drug-related mortality.

Illicitly manufactured fentanyl (IMF) is increasing in international drug supply chains, and IMF-related opioid overdose deaths are rising in North America. Hospitalizations among patients with opioid use disorder (OUD) are also rising; and, hospitalized patients are at increased risk of overdose and death following hospital discharge. Hospitalization is a key opportunity to engage patients with OUD. Addiction consult services (ACS) can provide effective treatment for patients hospitalized with OUD. This study aims to estimate the effect of increasing IMF contamination on drug-related death among patients hospitalized with OUD, and simulate the role of ACS expansion to mitigate these effects. We used a Markov model to mirror care systems for adult patients hospitalized with OUD in Oregon, from the time of hospital admission through 12-months post-discharge, and simulated patients through modeled care systems to evaluate the expansion of Addiction Consult Services in the context of increasing IMF in the drug supply. In a simulated cohort of 10,000 patients, we estimate that 537 patients would die from drug-related causes within 12-months of hospital discharge. In the context of increased IMF in the drug supply, this estimate increased to 913. ACS referral at baseline was 4%; increasing ACS referral to accommodate 10%, 50%, or 100% of hospitalized OUD patients in the state reduces drug-related deaths to 904, 849, and 780, respectively. The number needed to treat for ACS to avoid one drug-related death in the context of increased IMF was 73. Hospitals should expand interventions to help reduce IMF-related opioid overdoses, including through implementation of ACS. In the context of rising IMF-related deaths, ACS expansion could help connect patients to treatment, offer harm reduction interventions, or both, which can help reduce the risk of opioid-related death.

Using death scene and toxicology evidence to define involvement of heroin, pharmaceutical morphine, illicitly manufactured fentanyl and pharmaceutical fentanyl in opioid overdose deaths, 38 states and the District of Columbia, January 2018-December 2019.

Tracking specific drugs contributing to drug overdose deaths is limited when relying on death certificate (DC) data alone. This study aimed to determine whether integrating DC data with medical examiner/coroner reports, including postmortem toxicology and death investigation findings, would enhance identification of (1) heroin and pharmaceutical morphine involvement in overdose deaths and (2) fentanyl source (illicitly manufactured versus pharmaceutical). Retrospective analysis of heroin, pharmaceutical morphine, illicitly manufactured fentanyl (IMF) and pharmaceutical fentanyl involvement in fatal overdoses. DC and toxicology data were compared with enhanced definitions integrating overdose scene, witness and toxicology evidence. United States: 38 states and the District of Columbia, participating in Centers for Disease Control and Prevention (CDC)-funded opioid overdose death surveillance. Opioid overdose decedents from funded jurisdictions; deaths during 1 January 2018-31 December 2019. Using medical examiner/coroner report data, deaths with 6-acetylmorphine and/or morphine detected by postmortem toxicology were defined as confirmed, probable or suspected heroin deaths, or probable pharmaceutical morphine deaths. Fentanyl was defined as probable or suspected IMF or probable pharmaceutical fentanyl. The enhanced definition defined 18 393 deaths as confirmed, probable, or suspected heroin deaths (including 2678 with morphine listed as cause of death on the DC) and 404 as probable pharmaceutical morphine deaths. Among deaths with fentanyl detected, 89.3% were defined as probable or suspected IMF and 1.0% as probable pharmaceutical fentanyl. Fentanyl source could not be determined for 9.7% of deaths. Integrating drug overdose scene, witness and toxicology findings can improve identification of specific drugs contributing to overdose deaths and enhance overdose intervention targeting.

What Your Death Certificate Says About You May Be Wrong: A Narrative Review on CDC's Efforts to Quantify Prescription Opioid Overdose Deaths.

Mortality data in most countries are reported using the International Classification of Diseases (ICD), managed by the WHO. In this paper, we show how the ICD is ill-suited for classifying drug-involved deaths, many of which involve polysubstance abuse and/or illicitly manufactured fentanyl (IMF).Opioids identified in death certificates are categorized according to six ICD T-codes: opium (T40.0), heroin (T40.1), methadone (T40.3), other synthetic narcotics (T40.4), and other and unspecified narcotics (T40.6). Except for opium, heroin, and methadone, all other opioids except those that are unspecified are aggregated in two T-codes (T40.2 and T40.4), depending upon whether they are natural/semisynthetic or synthetic opioids other than methadone. The result is a system that obscures the actual cause of most drug overdose deaths and, instead, just tallies the number of times each drug is mentioned in an overdose situation.We examined the CDC’s methodology for coding other controlled substances according to the ICD and found that, besides fentanyl, the ICD does not distinguish between other licit and illicitly manufactured controlled substances. Moreover, we discovered that the CDC codes all methadone-related deaths as resulting from the prescribed form of the drug. These and other anomalies in the CDC’s mortality reporting are discussed in this report.We conclude that the CDC was at fault for failing to correct the miscoding of IMF. Finally, we briefly discuss some of the public policy consequences of this error, the misguided focus by public health and safety officials on pharmaceutical opioids, their prescribers and users, and the pressing necessity for the CDC to reassess how it measures and reports drug-involved mortality.

Illicitly Manufactured Fentanyl Entering the United States.

The 'third wave' of the ongoing opioid overdose crisis in the United States (US) is driven in large measure by illicitly manufactured fentanyl (IMF), a highly potent synthetic opioid or an analog developed in clandestine laboratories primarily in China and Mexico. It is smuggled into this country either as IMF or as precursors. The southern border of the US is a frequent point of entry for smuggled IMF and the amounts are increasing year over year. IMF is also sometimes mixed in with other substances to produce counterfeit drugs and dealers as well as end-users may not be aware of IMF in their products. IMF is inexpensive to produce and when mixed with filler materials can be used to cut heroin, vastly expanding profitability. It is an attractive product for smuggling as very tiny amounts can be extremely potent and highly profitable. Drug trafficking over the border also involves the tandem epidemic of money laundering as drugs enter the country and cash payments exit. While drug smuggling in and out of the US (and other nations) has been going on for decades, the patterns are changing. Highly potent and potentially lethal IMF is a dangerous new addition to the illicit drug landscape and one with disastrous consequences.

Consumer discernment of fentanyl in illicit opioids confirmed by fentanyl test strips: Lessons from a syringe services program in North Carolina.

The United States (U.S.) continues to witness an unprecedented increase in opioid overdose deaths driven by precipitous growth in the supply and use of illicitly-manufactured fentanyls (IMF). Fentanyl's growing market share of the illicit opioid supply in the U.S. has led to seismic shifts in the composition of the country's heroin supply. The growth in fentanyl supply has transformed illicit opioid markets once offering heroin with fairly consistent purity and potency to a supply overpopulated with fentanyl(s) of inconsistent and unpredictable potency. In response, people who inject drugs (PWID) have developed a number of sensory strategies to detect fentanyl in illicit opioids. The current study examined the accuracy of sensory discernment strategies by measuring study participants' descriptions of the last opioid injected and checked with a fentanyl test strip (FTS) by that test's positive/negative result. The primary objective was to determine associations between FTS results and descriptions of the illicit opioid's physical appearance and physiological effects. Between September-October 2017, a total of 129 PWID were recruited from a syringe services program in Greensboro, North Carolina and completed an online survey about their most recent use of FTS. Participants were instructed to describe the appearance and effects associated with the most recent opioid they injected and tested with FTS. We conducted bivariate and multivariate analyses to determine differences in positive vs negative FTS results and the physical characteristics and physiological experiences reported. An exploratory analysis was also conducted to describe the types and bodily locations of unusual sensations experienced by PWID reporting positive FTS results. For physical characteristics, 32% reported that the drug was white before adding water and 38% reported the solution was clear after adding water. For physiological effects compared to heroin, 42% reported a stronger rush, 30% a shorter high, 30% a shorter time to the onset of withdrawal symptoms, and 42% experienced unusual sensations. In the multivariable model adjusting for demographics and polydrug correlates, white color of drug before adding water, stronger rush, shorter time to withdrawal, and unusual sensations were significantly associated with a positive FTS result. The most common unusual sensations were pins and needles (51%), warming of the head and face (35%), and lightheadedness (30%), and the most common locations where sensations occurred were face and neck (61%), arms/legs (54%), and chest (37%). We found positive FTS results were significantly associated with the physical characteristics and physiological effects described by PWID. Descriptions concerning physical appearance were consistent with law enforcement profiles of illicitly-manufactured fentanyl and physiological effects were concomitant with scientific and clinical medical literature on iatrogenic fentanyl use. Taken together, these findings suggest sensory strategies for detecting fentanyl in illicit opioids may be an effective risk reduction tool to help consumers navigate unpredictable markets more safely.

Cannabis use is associated with reduced risk of exposure to fentanyl among people on opioid agonist therapy during a community-wide overdose crisis

BackgroundThe ongoing opioid overdose crisis is driven largely by exposure to illicitly-manufactured fentanyl. Preliminary observational and experimental research suggests that cannabis could potentially play a role in reducing use of prescription opioids among individuals with chronic pain. However, there is limited data on the effects of cannabis on illicit opioid consumption, particularly fentanyl, especially among individuals on opioid agonist therapy (OAT). We sought to assess the longitudinal association between cannabis use and exposure to fentanyl among people on OAT. MethodsData were drawn from two community-recruited prospective cohorts of people who use drugs in Vancouver, Canada. We used generalized linear mixed-effects modeling, adjusted by relevant confounders, to investigate the relationship between cannabis use and recent fentanyl exposure (both assessed by urine drug testing) among participants on OAT between 2016 and 2018. ResultsAmong the 819 participants on OAT who contributed 1989 observations over the study period, fentanyl exposure was common. At the baseline interview, fentanyl was detected in a majority of participants (431, 53 %), with lower prevalence among individuals with urine drug tests positive for tetrahydrocannabinol (47 vs. 56 %, p = 0.028). Over all study interviews, cannabis use was independently associated with reduced likelihood of being recently exposed to fentanyl (Adjusted Prevalence Ratio = 0.91, 95 % Confidence Interval: 0.83 – 0.99). ConclusionsParticipants on OAT using cannabis had significantly lower risk of being exposed to fentanyl. Our findings reinforce the need for experimental trials to investigate the potential benefits and risks of controlled cannabinoid administration for people on OAT.

Barriers and facilitators to a novel low-barrier hydromorphone distribution program in Vancouver, Canada: a qualitative study

BackgroundNorth America is experiencing an overdose crisis driven by illicitly-manufactured fentanyl, related analogues, and fentanyl-adulterated drugs. The concept of ‘safe supply’ has been suggested as a potential measure to address the overdose crisis by providing a regulated alternative to illicit opioids to people at high risk of fatal overdose. In January 2019, a novel hydromorphone tablet distribution program was implemented within an overdose prevention site in Vancouver, Canada’s Downtown Eastside neighbourhood. This study explored barriers and facilitators to engagement with this program. MethodsIn-depth interviews were conducted with 42 participants enrolled in the hydromorphone tablet distribution program, and over 100 h of ethnographic observation were conducted in and around the study site. Thematic analysis of the interviews and ethnographic observation focused on program operation, including barriers and facilitators to program uptake, access, and engagement. ResultsBarriers to program engagement identified include: limited operating hours and dose schedule, co-location within the overdose prevention site (e.g., wait times), and receiving the generic formulation of hydromorphone. Facilitators identified include: having access to a reliable source of opioids, co-location within the overdose prevention site (e.g., low-barrier design), experiences of agency, and program flexibility. ConclusionOur findings demonstrate key implementation and operational considerations of safe supply programs. In particular, lower-barrier design and operational features should be considered to improve uptake and engagement. Safe opioid supply programs are a promising intervention to address North America’s ongoing overdose crisis by providing people at high risk of fatal overdose an alternative to the toxic drug supply.

Non-prescription Fentanyl Positive Toxicology: Prevalence, Positive Predictive Value of Fentanyl Immunoassay Screening, and Description of Co-substance Use.

Opioid overdose deaths in Massachusetts linked to illicitly-manufactured fentanyl have increased dramatically. In response, an urban safety-net hospital added urine fentanyl testing with reflex confirmation testing to its standard urine toxicology panel. The goals of this study were to describe fentanyl toxicology test results, identify the positive predictive value of presumptive fentanyl immunoassay, and describe co-substance use among those with unexpected fentanyl positive results. We included urine toxicology tests from January through June 2016 analyzed at an urban safety-net hospital. We excluded tests from individuals prescribed or administered fentanyl within the preceding 72 hours. Positive fentanyl immunoassay tests underwent reflex chromatography confirmation testing. Samples that confirmed positive for acetyl fentanyl and/or fentanyl and/or norfentanyl were considered true positives. Of 11,873 urine samples, 10.4% of samples screened fentanyl positive and 8.8% were confirmed fentanyl positive. The positive predictive value of a positive urine fentanyl screen was 85.7%. Of 4398 unique patients, 13.2% had at least 1 test confirmed positive for nonprescription fentanyl. Patients with a confirmed fentanyl positive drug test were more likely to have positive urine drug test for barbiturates, benzodiazepines, cocaine, methadone, and opiates, and less likely to have oxycodone or buprenorphine. At an urban safety-net hospital, nonprescription fentanyl use was common and was associated with greater use of other substances favoring routine fentanyl testing. Although the positive predictive value of the screening test was high, confirmation testing detected substantial numbers of false positives, especially in older patients. Therefore, fentanyl confirmation testing should be used when results will change treatment approach and patient education.