Pharmaceutical Fentanyl Research Articles

B-298 Retrospective Analysis of Fentanyl Positivity at a Large Academic Center Reveals Trends in Illicit Fentanyl Use

Abstract Background National drug-involved overdose deaths continue to rise with deaths involving synthetic opioids (primarily fentanyl) showing the most significant upward trend. Fentanyl is a synthetic opioid with short-acting analgesic activity and a 50–100 times higher potency compared to morphine. Pharmaceutical fentanyl is typically used to treat patients with severe or chronic pain. In contrast, “illegal” fentanyl has frequently been added to other drugs including heroin, cocaine, methamphetamine, and MDMA to increase their potency and contributing to overdose deaths. In this study, we have investigated trends in fentanyl and fentanyl analogs positivity at a large academic medical center. Methods Retrospective analysis of results reported over seven years (2015–2021) for untargeted urine drug screens included testing performed for acute exposure and compliance. Presence of fentanyl, fentanyl analogs, and other prescribed or illicit used drugs was determined by gas chromatography—mass spectrometry (GCMS). Overall positivity was calculated as a percentage of total reported results. Results Fentanyl, and fentanyl analog positivity was determined for 40 782 urine drug screen results. Overall positivity for fentanyl and fentanyl analogs increased 3.8-fold over the past seven year from 1.53% (2015) to 5.78% (2021). Co-positivity with other illicit drugs such as cocaine and heroin also increased from 7% and 8% respectively, in 2015, to 42% and 13%, in 2021. Presence of fentanyl analogs such as fluorofentanyl, despropionylfentanyl, and acetylfentayl increased in the recent years as well. Conclusion Our data reveals increased positivity of fentanyl and fentanyl analogs present with cocaine, heroin, or their metabolites suggesting increased use of illicit fentanyl. The high prevalence supports the inclusion of fentanyl on routine urine drug screen immunoassays, or at a minimum as a reflex with a positive opiate screen.

Monitoring for fentanyl within Australian supervised injecting facilities: Findings from feasibility testing of novel methods and collaborative workshops

Australia is yet to see widespread fentanyl-contaminated heroin, despite the established presence of fentanyl in other countries. International mortality trends alongside a local cluster of fentanyl-related deaths prompted interest in developing methods to monitor for fentanyl and other potentially harmful novel psychoactive substances (NPS) in Australia. We tested novel methods to monitor for fentanyl and other NPS. From 2017-2021, clients from supervised injecting facilities (SIFs) in Melbourne and Sydney, Australia, contributed urine screens (UDS) with BTNX Rapid Response™ fentanyl test strips (FTS) paired with surveys, and injecting equipment associated with opioid overdoses for laboratory analysis. A single site piloted drug checking using FTS with laboratory confirmation. Two workshops were conducted with SIF staff, content experts and people with lived experience to determine how results can inform practices within SIFs. Of the 911 UDS with FTS conducted, less than 1% (n=8) yielded positive results that were not explained by self-reported pharmaceutical fentanyl use, with two laboratory confirmed fentanyl positive results. Injecting equipment from 59 overdoses was tested and neither fentanyl nor other NPS were identified. Drug checking with FTS (n=34) indicated the presence of fentanyl on three tests. Two specimens were subsequently sent for laboratory testing and classified as false positives as the presence of fentanyl was not confirmed. Workshop participants (n=21) felt routine monitoring with FTS currently had limited value. A process for using pre-defined signals to trigger surveillance was developed. The high false positive rates with FTS, relative to the small number of positive results and potential for them to undermine confidence in FTS emphasised the need for confirmatory testing. The role of routine surveillance was unclear within the current low-fentanyl context, however, a process was developed to upscale testing should signals of increased fentanyl prevalence in the Australian heroin market emerge.

Twenty-year trends in pharmaceutical fentanyl and illicit fentanyl deaths, Australia 2001-2021.

Increasing overdose deaths attributable to illicitly manufactured fentanyl and fentanyl analogues in North America has driven international concern about the expansion of these substances into drug markets elsewhere. This paper investigates 20-year trends in fentanyl deaths in Australia, distinguishing between deaths attributable to pharmaceutical, and to illicitly manufactured fentanyl and fentanyl analogues. Analysis of fentanyl overdose deaths (2001-2021), extracted from the National Coronial Information System (NCIS). 833 fentanyl-related deaths were identified, predominantly occurring among males (73%), and people with a history of injecting drug use (67%). Rates of fentanyl deaths significantly increased between 2001 and 2014 and declined between 2015 and 2021. Drug dependence remained the most significant factor in deaths among people with a history of injecting drug use (87% vs 23% without such a history), while having died by suicide was the most significant factor for those without a history of injecting drug use (20% vs 4% respectively). Three quarters (72%) of deaths were attributable to pharmaceutical fentanyl and 21% to probable pharmaceutical fentanyl, with 5% attributable to fentanyl analogues (3%) (predominantly furanylfentanyl and acetylfentanyl) and illicitly manufactured fentanyl (2%). Deaths attributable to illicitly manufactured fentanyl and fentanyl analogues occurred from 2013 onwards. Pharmaceutical fentanyl deaths in Australia have declined since 2015, in parallel with overall declines in pharmaceutical opioids (including fentanyl) dispensed since 2014. Deaths continue to occur among people with a history of injecting drug use and drug dependence. Deaths attributable to illicit fentanyl have emerged since 2013 but remain low in comparison to pharmaceutical fentanyl deaths.

Correlates of heroin use, pharmaceutical fentanyl misuse, and dual heroin-fentanyl use: evidence from the USA

PurposeThe emergence of fentanyl has deepened concerns about the opioid crisis. The shift has created new distinctions in patterns of opioid use, which may be important for prevention and intervention. This paper aims to examine sociodemographic correlates as well as health and substance use characteristics of different groups of opioid users.Design/methodology/approachThis paper used the 2015–2019 National Survey on Drug Use and Health to examine distinctions between groups (n = 11,142) of individuals who misuse prescription opioids, use heroin but not fentanyl, misuse pharmaceutical fentanyl but not heroin and use both heroin and fentanyl. Multinomial and logistic regression models were used to identify these distinctions.FindingsFew sociodemographic differences emerged between the prescription opioid group and pharmaceutical fentanyl misuse group. While those who misuse fentanyl have higher odds of using other drugs and experiencing certain mental health problems than those misusing prescription pills, both the heroin and fentanyl–heroin use groups reported considerably poorer health and substance use indicators relative to those who solely misuse fentanyl. It is also notable that both heroin use groups are more highly associated with cocaine and methamphetamine use than those misusing fentanyl alone.Research limitations/implicationsWhile this study identifies important distinctions between the opioid use groups studied, individuals using both heroin and pharmaceutical fentanyl report the poorest health and substance use characteristics. Important differences between the fentanyl-only group and the group who consume both drugs may have implications for prevention, intervention and clinical work amid shifting patterns of opioid use.Practical implicationsImportant differences between the fentanyl-only group and the group who consume both drugs may have implications for prevention, intervention and clinical work amid shifting patterns of opioid use.Originality/valueThis study highlights distinctions between pharmaceutical fentanyl users, heroin users and users of both substances.

Accidental Occupational Exposure to a Large Volume of Liquid Fentanyl on a Compromised Skin Barrier with No Resultant Effect.

The high prevalence of fentanyl in the illicit drug supply has generated concern among first responders regarding occupational exposure. Social media sharing of unconfirmed first responder overdoses after brief exposure to fentanyl may be contributing to an inappropriate risk perception of brief dermal fentanyl exposure. This case details a dermal exposure to a large dose of analytically confirmed pharmaceutical fentanyl (fentanyl citrate, 10 microgram fentanyl base per ml), over a large skin surface area. Additionally, the exposure occurred at a site with some skin barrier compromise, a factor that can increase fentanyl absorption. The patient underwent appropriate decontamination and underwent a brief medical assessment with no clinical effects of opioid exposure observed. This information is of value to first responders and other health care workers who are at risk of occupational fentanyl exposure. Findings are consistent with in vitro and ex vivo data supporting low risk of rapid absorption after brief dermal fentanyl exposure.

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.

Sentanyl: a comparison of blood fentanyl concentrations and naloxone dosing after non-fatal overdose

Introduction Non-pharmaceutical fentanyl and its analogs have driven striking increases in opioid-associated overdose deaths. These highly potent opioids can be found at low concentrations in biological specimens. Little is known regarding the concentrations of these substances among survivors of non-fatal overdoses. In a locale where fentanyl is responsible for the majority of non-fatal opioid overdoses, we compared the concentration of fentanyl in blood to naloxone dosing in the presence and absence of a concurrent sedative-hypnotic exposure. Methods In this pilot study, we enrolled adult patients presenting to the emergency department (ED) who: (1) arrived after an overdose requiring naloxone for the reversal of respiratory depression; and (2) who required venipuncture or intravenous access as part of their clinical care. Blood specimens (n = 20) underwent comprehensive toxicology testing, including the quantitation of fentanyl, fentanyl analogs, and naloxone, as well as the detection of common sedative-hypnotics and a wide range of other illicit and pharmaceutical substances. We then compared fentanyl concentrations to naloxone dosing in participants with and without a concomitant sedative-hypnotic exposure. Results Nineteen of twenty participants (95%) were exposed to fentanyl prior to their overdose; the remaining participant tested positive for heroin metabolites. No participants reported pharmaceutical fentanyl use. Fentanyl analogs – acetylfentanyl or carfentanil – were present in three specimens. In 11 cases, fentanyl and its metabolites were the only opioids identified. Among the fentanyl-exposed, blood concentrations ranged from <0.1–19 ng/mL with a mean of 6.2 ng/mL and a median of 3.6 ng/mL. There was no relationship between fentanyl concentration and naloxone dose administered for reversal. We detected sedative-hypnotics (including benzodiazepines, muscle relaxants, and antidepressants) in nine participants. Among the sedative-hypnotic exposed, fentanyl concentrations were lower, but naloxone dosing was similar to those without a concomitant exposure. Conclusions In this study, we found that: 1) fentanyl was present in the blood of nearly all participants; 2) fentanyl concentrations were lower among study participants with concomitant sedative-hypnotic exposure; and 3) the dose of naloxone administered for overdose reversal was not associated with the measured fentanyl concentration in blood specimens. Our results underscore the role that tolerance and concomitant drug exposure play in the precipitation and resuscitation of management of opioid overdose.

Microinduction of Buprenorphine/Naloxone: A Review of the Literature.

Buprenorphine's high-binding affinity as a partial µ-opioid agonist displaces preexisting full agonists causing precipitated withdrawal, which requires most individuals starting buprenorphine to endure moderate withdrawal prior to induction to avoid precipitated withdrawal. A novel approach called microinduction has emerged to remove this prerequisite. Our aim is to review the literature on these alternative approaches. Using keywords including buprenorphine, buprenorphine/naloxone, transdermal buprenorphine, suboxone, microinduction, microdosing, rapid induction, buprenorphine-dosing protocol, the authors searched PubMed/Medline, EMBASE, PsycINFO, PsychARTICLES, and Scopus databases from the date of inception through April 30, 2020, which yielded 1726 results, which, in turn, after manual exclusion for irrelevant content and publication in languages other than English, generated a total of 18 papers. On the basis of 18 papers included in this review, 63 patients were successfully transitioned to buprenorphine using different microdosing techniques, primarily in the inpatient setting. From the available data, patients were transitioned from a variety of opioids over a range of dosing without significant withdrawal, and initial doses ranged most frequently from 0.2 to 0.5 mg. While the timeframe for the various schedules ranged from 3 to 112 days, most transitioned over a period of 4 to 8 days, and most participants completed the cross titration at 8 to 16 mg. The growing literature demonstrates some initial promise for alternative induction models, specifically targeting patients averse to withdrawal, patients prescribed opioids for chronic pain, patients on high-dose methadone, and patients using illicit or pharmaceutical fentanyl. This manuscript provides a review of the existing literature to help clinicians better understand the approaches to microdosing of buprenorphine in various clinical settings and populations. (Am J Addict 2020;00:00-00).

A deadly trend in fentanyl fatalities (England, 1998-2017).

To identify trends in drug-related deaths associated with fentanyl and its derivatives, including novel variants, in England, 1998-2017. Case reports from the National Programme on Substance Abuse Deaths (NPSAD) where a pharmaceutical fentanyl or non-pharmaceutical fentanyl derivative (NPFD) was found at post-mortem and/or implicated in the death were extracted for analysis. NPSAD has received case reports detailing 298 deaths in England from 1998-2017 where a fentanyl was found at post-mortem and/or implicated in the death. Hospital administered fentanyl is "very safe", whereas pharmaceutical fentanyls in the community, procured either legitimately via prescription or illegitimately, carry high risk of unintentional death. Deaths involving NPFDs, which possess extreme potencies in comparison to morphine, have drastically risen over the past three years, and correlate with an increasing number of available compounds. Males, and those with existing opioid abuse disorders, are particularly susceptible to death related to NPFD intake. The increasing availability of both pharmaceutical fentanyls and NPFDs represents a serious risk to public health. Unintentional misuse of these compounds in England is contributing to the exponential increase in fentanyl-associated deaths that is being observed at the global scale.

Characteristics and circumstances of heroin and pharmaceutical opioid overdose deaths: Comparison across opioids

BackgroundAlthough much is known about the correlates of heroin overdose, less is known about pharmaceutical opioid (PO) overdose. This study aimed to examine correlates of opioid overdose deaths by opioid and compare correlates between opioids. MethodsAnalysis of opioid overdose deaths in Australia between 2000–2015, extracted from the National Coronial Information System (NCIS). The NCIS is an online database of deaths reportable to the coroner, and contains coroner’s findings, autopsy and toxicology reports. Deaths were categorized into mutually exclusive groups: 1) Heroin deaths; and 2) PO deaths (excluding heroin). PO deaths were examined by individual opioid. ResultsThere were 10,795 opioid overdose deaths over the study period. Relative to deaths occurring in major cities, deaths in regional/remote areas had 15.2 (95 % CI: 11.5–20.2) times the risk of being attributed to pharmaceutical fentanyl than heroin. Relative to deaths among people without a recorded history of chronic pain, deaths among people with a recorded history of chronic pain had a 1.9–10.7-fold increased risk of the death being attributed to POs than heroin. Deaths among people with a recorded history of substance use problems where the opioid was injected prior to death had 7.2 and 1.7 times the risk of being attributed to methadone and pharmaceutical fentanyl (respectively) than heroin. ConclusionsFindings suggest the need to: educate PO consumers about the risks of overdose at the time of prescribing; increase coverage and engagement in opioid dependence treatment (particularly in regional/remote areas); and increase uptake of take-home naloxone to reduce opioid overdose mortality.

Overdose Deaths Related to Fentanyl and Its Analogs - Ohio, January-February 2017.

Ohio is experiencing unprecedented loss of life caused by unintentional drug overdoses (1), with illicitly manufactured fentanyl (IMF) emerging as a significant threat to public health (2,3). IMF is structurally similar to pharmaceutical fentanyl, but is produced in clandestine laboratories and includes fentanyl analogs that display wide variability in potency (2); variations in chemical composition of these drugs make detection more difficult. During 2010-2015, unintentional drug overdose deaths in Ohio increased 98%, from 1,544 to 3,050.* In Montgomery County (county seat: Dayton), one of the epicenters of the opioid epidemic in the state, unintentional drug overdose deaths increased 40% in 1 year, from 249 in 2015 to 349 in 2016 (estimated unadjusted mortality rate=57.7 per 100,000) (4). IMFs have not been part of routine toxicology testing at the coroner's offices and other types of medical and criminal justice settings across the country (2,3). Thus, data on IMF test results in the current outbreak have been limited. The Wright State University and the Montgomery County Coroner's Office/Miami Valley Regional Crime Laboratory (MCCO/MVRCL) collaborated on a National Institutes of Health study of fentanyl analogs and metabolites and other drugs identified in 281 unintentional overdose fatalities in 24 Ohio counties during January-February 2017. Approximately 90% of all decedents tested positive for fentanyl, 48% for acryl fentanyl, 31% for furanyl fentanyl, and 8% for carfentanil. Pharmaceutical opioids were identified in 23% of cases, and heroin in 6%, with higher proportions of heroin-related deaths in Appalachian counties. The majority of decedents tested positive for more than one type of fentanyl. Evidence suggests the growing role of IMFs, and the declining presence of heroin and pharmaceutical opioids in unintentional overdose fatalities, compared with 2014-2016 data from Ohio and other states (3-5). There is a need to include testing for IMFs as part of standard toxicology panels for biological specimens used in the medical, substance abuse treatment, and criminal justice settings.

Misuse of Novel Synthetic Opioids: A Deadly New Trend.

Novel synthetic opioids (NSOs) include various analogs of fentanyl and newly emerging non-fentanyl compounds. Together with illicitly manufactured fentanyl (IMF), these drugs have caused a recent spike in overdose deaths, whereas deaths from prescription opioids have stabilized. NSOs are used as stand-alone products, as adulterants in heroin, or as constituents of counterfeit prescription medications. During 2015 alone, there were 9580 deaths from synthetic opioids other than methadone. Most of these fatalities were associated with IMF rather than diverted pharmaceutical fentanyl. In opioid overdose cases, where the presence of fentanyl analogs was examined, analogs were implicated in 17% of fatalities. Recent data from law enforcement sources show increasing confiscation of acetylfentanyl, butyrylfentanyl, and furanylfentanyl, in addition to non-fentanyl compounds such as U-47700. Since 2013, deaths from NSOs in the United States were 52 for acetylfentanyl, 40 for butyrylfentanyl, 128 for furanylfentanyl, and 46 for U-47700. All of these substances induce a classic opioid toxidrome, which can be reversed with the competitive antagonist naloxone. However, due to the putative high potency of NSOs and their growing prevalence, it is recommended to forgo the 0.4 mg initial dose of naloxone and start with 2 mg. Because NSOs offer enormous profit potential, and there is strong demand for their use, these drugs are being trafficked by organized crime. NSOs present major challenges for medical professionals, law enforcement agencies, and policymakers. Resources must be distributed equitably to enhance harm reduction though public education, medication-assisted therapies, and improved access to naloxone.

Prevalence and correlates of fentanyl-contaminated heroin exposure among young adults who use prescription opioids non-medically

BackgroundThe rate of overdose deaths caused by fentanyl-contaminated heroin (FCH) use is increasing rapidly in the United States. We examined risk factors for exposure to FCH and experiences with FCH use among young adult non-medical prescription opioids (NMPO) users. MethodsWe analyzed data from the Rhode Island Young Adult Prescription Drug Study (RAPiDS), which enrolled young adults aged 18 to 29 reporting prior 30day NMPO use between January 2015 and February 2016. Participants completed questionnaires ascertaining drug use patterns and risk behaviors, including FCH exposure. Logistic regression was used to assess factors associated with known or suspected FCH exposure. ResultsOf 199 participants, the median age was 25 (IQR: 22, 27), 130 (65.3%) were male, and 122 (61.3%) were of White, non-Hispanic race/ethnicity. In total, 22 (11%) reported known or suspected FCH exposure in the prior six months. Several drug use patterns and risk behaviors were associated with FCH exposure, including: regular heroin and cocaine use; diverted pharmaceutical fentanyl use in the prior six months; NMPO use to avoid withdrawal symptoms; longer duration of NMPO use; regular injection drug use; and prior overdose (all p<0.001). Among participants who reported FCH exposure, 59% were unaware that their heroin was contaminated with fentanyl prior to last use, 59% reported that FCH provides a better high, and all recognized that fentanyl increases overdose risk. ConclusionsExposure to fentanyl-contaminated heroin is an emerging trend among young adult NMPO users in Rhode Island. Overdose prevention programs addressing FCH use are urgently needed.

Increases in Fentanyl-Related Overdose Deaths - Florida and Ohio, 2013-2015.

In March and October 2015, the Drug Enforcement Administration (DEA) and CDC issued nationwide alerts identifying fentanyl, particularly illicitly manufactured fentanyl (IMF), as a threat to public health and safety (1,2). IMF is pharmacologically similar to pharmaceutical fentanyl (PF), but is unlawfully produced in clandestine laboratories, obtained via illicit drug markets, and includes fentanyl analogs. Fentanyl is a synthetic opioid 50-100 times more potent than morphine and approved for the management of surgical/postoperative pain, severe chronic pain, and breakthrough cancer pain.* DEA's National Forensic Laboratory Information System (NFLIS) collects drug identification results from drug cases analyzed by federal, state, and local forensic laboratories throughout the United States.(†) In 2014, 80% of fentanyl submissions (i.e., drug products obtained by law enforcement that tested positive for fentanyl) in NFLIS were identified from 10 states, including Florida and Ohio (2), and seven of these 10 states reported sharp increases in fentanyl-related overdose deaths (fentanyl deaths) (3). This report presents findings of increased fentanyl deaths during 2013-2015 from investigations conducted by the University of Florida and the Ohio Department of Public Health, in collaboration with CDC. Analyses examined the association between trends in fentanyl-related law enforcement submissions and fentanyl deaths and describes groups at risk for fentanyl death using medical examiner and coroner reports. The marked increases in fentanyl death in Florida and Ohio during 2013-2015 were closely associated with parallel increases in fentanyl submissions, with the largest impact on persons who use heroin, consistent with reports that IMF is commonly mixed with or sold as heroin (1,4). In Ohio, circumstances associated with fentanyl deaths included a current diagnosed mental health disorder(§) and recent release from an institution such as a jail, rehabilitation facility, or hospital.

Fentanyl: A Review for Clinical and Analytical Toxicologists

Fentanyl is a highly potent, short acting synthetic analgesic indicated as a preanesthetic medication. It is available for intravenous injection, as a transdermal patch and a lozenge dosage form. Fentanyl displays a large apparent volume of distribution, short plasma half life and extensive biotransformation. It is a popular drug of abuse among health care professionals. Diversion of pharmaceutical fentanyl preparations, as well as the availability of illicitly synthesized potent and highly toxic fentanyl analogs have resulted in numerous overdose deaths. Analysis of fentanyl and fentanyl analogs requires highly selective and sensitive methodologies. This review is intended as a quick reference source for clinical and analytical toxicologists.