1. What is Fentanyl?

"Fentanyl is a synthetic opioid analgesic acting predominately at the μ-opiate receptor. It has historically been used as a pain reliever and an anaesthetic in both human and veterinary medicine and in terms of analgesic activity it is at least 80 times more potent than morphine. Fentanyl was first synthesized by Paul Janssen in 1960 and marketed as a medicinal product for treating pain. Subsequently, many fentanyl analogues were developed including sufentanil, alfentanil, remifentanil, and carfentanil. Fentanyl was first introduced for widespread palliative use in the mid-1990s in the form of transdermal patches, and to this day, it continues to be an important and much prescribed pain management medication in many countries. Concern surrounding the fentanyls is linked to their potential for dependence and misuse, their high potency and associated risk of fatal overdose."

Jane Mounteney, Isabelle Giraudon, Gleb Denissov, and Paul Griffiths, "Fentanyls: Are we missing the signs? Highly potent and on the rise in Europe," International Journal of Drug Policy, Volume 26, Issue 7, 626 - 631. doi: 10.1016/j.drugpo.2015.04.003. Epub 2015 Apr 17.

2. Fentanyl Analogs, Other Synthetic Opioids, and Research Opioids

"Opioids are a group of drugs comprising a range of substances, including opiates and their synthetic analogues. Opiates are the naturally occurring alkaloids found in the opium poppy and include morphine, codeine and thebaine. Their semi-synthetic derivatives include heroin, hydrocodone, oxycodone and buprenorphine. Opioids also include a range of synthetic or pharmaceutical opioids, such as methadone, pethidine, tramadol and fentanyl.119

"The group also comprises a diverse group of chemicals – opioid receptor agonists – that were initially developed by pharmaceutical companies with the aim of producing more effective opioids for pain management, but were later discarded or considered unsuitable for further development.120 Many of those substances, also known as research opioids, novel synthetic opioids or NPS opioids, are considered to be more potent than morphine; synthetic opioids that are analogues of fentanyl are considered to be 50–100 times more potent than morphine.121, 122, 123 Research or NPS opioids such as U-47700, AH-7921, fentanyl analogues (acrylfentanyl, butyrylfentanyl), the new class of benzimidazole (isotonitazene)124 and the more recent brorphine,125 to name but a few, have added to the ever-increasing complexity of opioids, both in terms of controlling the misuse of these substances and their public health implications. Many of the research opioids, such as U-47700 or butyrylfentanyl, have been put under international control in recent years, however. Moreover, some of the substances, such as W-15 and W-18, were initially introduced as potent opioids but were later found to have no activity on the opioid receptors, although they were put under national control in some countries.126 Nevertheless, research opioids are among the fastest increasing group among the wider new psychoactive substances identified or reported each year.127, 128"

United Nations Office on Drugs and Crime. World Drug Report 2021. Booklet Three: Drug Market Trends: Cannabis, Opioids. United Nations publication, Sales No. E.21.XI.8.

3. Growth of Fentanyl Related Deaths in the US

"Preliminary estimates of U.S. drug overdose deaths exceeded 60,000 in 2016 and were partially driven by a fivefold increase in overdose deaths involving synthetic opioids (excluding methadone), from 3,105 in 2013 to approximately 20,000 in 2016 (1,2). Illicitly manufactured fentanyl, a synthetic opioid 50–100 times more potent than morphine, is primarily responsible for this rapid increase (3,4). In addition, fentanyl analogs such as acetylfentanyl, furanylfentanyl, and carfentanil are being detected increasingly in overdose deaths (5,6) and the illicit opioid drug supply (7). Carfentanil is estimated to be 10,000 times more potent than morphine (8). Estimates of the potency of acetylfentanyl and furanylfentanyl vary but suggest that they are less potent than fentanyl (9). Estimates of relative potency have some uncertainty because illicit fentanyl analog potency has not been evaluated in humans."

Julie K. O’Donnell, PhD; John Halpin, MD; Christine L. Mattson, PhD; Bruce A. Goldberger, PhD; R. Matthew Gladden, PhD. Deaths Involving Fentanyl, Fentanyl Analogs, and U-47700 — 10 States, July–December 2016. Morbidity and Mortality Weekly Report. Vol. 66. Centers for Disease Control. October 27, 2017.

4. Federal Offenses Involving Fentanyl

"While fentanyl and fentanyl analogue offenders remain a small proportion of the overall federal drug trafficking caseload (5.8%), the number of fentanyl offenders and fentanyl analogue offenders has increased sharply over the last several years. As reflected in Figure 10, the prevalence of fentanyl was flat for the ten years from 2005 through 2014. Over the next five years, the trend shifted. Beginning in 2015, the number of fentanyl offenders more than doubled each fiscal year. By fiscal year 2019, the Commission recorded 886 fentanyl drug trafficking offenders, a 3,592 percent increase from 24 offenders in fiscal year 2015.123

"The number of fentanyl analogue offenders also has increased precipitously in recent years. The number of such offenders was also largely stable from fiscal year 2012, the year the Commission first recorded a fentanyl analogue offender, through fiscal year 2016. Since fiscal year 2016, however, fentanyl analogue offenders increased 5,725 percent, from four offenders in fiscal year 2016 to 233 offenders in fiscal year 2019."

Fentanyl and Fentanyl Analogues: Federal Trends and Trafficking Patterns." US Sentencing Commission. January 2021.

5. Demographic Characteristics of People Charged With Federal Offenses Involving Fentanyl

"Race and citizenship patterns for fentanyl and fentanyl analogue offenders (Figure 13) differed compared to other drug offenders. Most notably, Black offenders constituted a greater proportion of fentanyl and fentanyl analogue offenders (40.5% and 58.9%, respectively) than other drug offenders (26.5%). Conversely, Hispanic offenders represented a smaller proportion of both fentanyl and fentanyl analogue offenders (33.9% and 9.1%, respectively), compared to other drug offenders (44.9%). U.S. citizens were more prominent in fentanyl (85.1%) and fentanyl analogue (96.1%) offenders compared to other drug offenders (78.3%).

"When focusing just on the comparison of fentanyl and fentanyl analogue offenders, Black offenders represented the largest group of both fentanyl (40.5%) and fentanyl analogue (58.9%) offenders. However, the representation of Hispanic offenders varied significantly, with Hispanics accounting for 33.9 percent of fentanyl offenders compared to 9.1 percent of fentanyl analogue offenders. This difference among the two groups in part reflects that fentanyl analogue offenders were somewhat more likely to be U.S. citizens (96.1%) compared to fentanyl offenders (85.1%)."

Fentanyl and Fentanyl Analogues: Federal Trends and Trafficking Patterns." US Sentencing Commission. January 2021.

6. Drug Quantity for Fentanyl Offenses

"Drug quantity varied considerably between fentanyl and its analogues.134 The drug quantity for fentanyl offenders in fiscal year 2019 ranged from 100 micrograms to 36 kilograms. The average drug weight for the fentanyl offenders was 1.7 kilograms, and the median drug weight was 160 grams (Figure 15).

"The drug quantity for fentanyl analogue offenders ranged from 70 milligrams to 62.1 kilograms. The average amount of fentanyl analogue trafficked was 764 grams and the median weight was 75 grams.

"These weights are not limited to the quantity of pure fentanyl or one of its analogues involved in an offense135 as these substances are often mixed with other drugs or cutting agents,136 or are pressed into pills with inert fillers. As discussed above, under the drug trafficking guidelines, the entire weight of any mixture or substance containing a detectable amount of the controlled substance is assigned to the controlled substance that results in the greater offense level.137"

Fentanyl and Fentanyl Analogues: Federal Trends and Trafficking Patterns." US Sentencing Commission. January 2021.

7. Involvement of Fentanyl in Overdose Deaths in the US

"Fentanyl was detected in 56.3% of 5,152 opioid overdose deaths in the 10 states during July–December 2016 (Figure). Among these 2,903 fentanyl-positive deaths, fentanyl was determined to be a cause of death by the medical examiner or coroner in nearly all (97.1%) of the deaths. Northeastern states (Maine, Massachusetts, New Hampshire, and Rhode Island) and Missouri** reported the highest percentages of opioid overdose deaths involving fentanyl (approximately 60%–90%), followed by Midwestern and Southern states (Ohio, West Virginia, and Wisconsin), where approximately 30%–55% of decedents tested positive for fentanyl. New Mexico and Oklahoma reported the lowest percentage of fentanyl-involved deaths (approximately 15%–25%). In contrast, states detecting any fentanyl analogs in >10% of opioid overdose deaths were spread across the Northeast (Maine, 28.6%, New Hampshire, 12.2%), Midwest (Ohio, 26.0%), and South (West Virginia, 20.1%) (Figure) (Table 1).

"Fentanyl analogs were present in 720 (14.0%) opioid overdose deaths, with the most common being carfentanil (389 deaths, 7.6%), furanylfentanyl (182, 3.5%), and acetylfentanyl (147, 2.9%) (Table 1). Fentanyl analogs contributed to death in 535 of the 573 (93.4%) decedents. Cause of death was not available for fentanyl analogs in 147 deaths.†† Five or more deaths involving carfentanil occurred in two states (Ohio and West Virginia), furanylfentanyl in five states (Maine, Massachusetts, Ohio, West Virginia, and Wisconsin), and acetylfentanyl in seven states (Maine, Massachusetts, New Hampshire, New Mexico, Ohio, West Virginia, and Wisconsin). U-47700 was present in 0.8% of deaths and found in five or more deaths only in Ohio, West Virginia, and Wisconsin (Table 1). Demographic characteristics of decedents were similar among overdose deaths involving fentanyl analogs and fentanyl (Table 2). Most were male (71.7% fentanyl and 72.2% fentanyl analogs), non-Hispanic white (81.3% fentanyl and 83.6% fentanyl analogs), and aged 25–44 years (58.4% fentanyl and 60.0% fentanyl analogs) (Table 2).

"Other illicit drugs co-occurred in 57.0% and 51.3% of deaths involving fentanyl and fentanyl analogs, respectively, with cocaine and confirmed or suspected heroin detected in a substantial percentage of deaths (Table 2). Nearly half (45.8%) of deaths involving fentanyl analogs tested positive for two or more analogs or fentanyl, or both. Specifically, 30.9%, 51.1%, and 97.3% of deaths involving carfentanil, furanylfentanyl, and acetylfentanyl, respectively, tested positive for fentanyl or additional fentanyl analogs. Forensic investigations found evidence of injection drug use in 46.8% and 42.1% of overdose deaths involving fentanyl and fentanyl analogs, respectively. Approximately one in five deaths involving fentanyl and fentanyl analogs had no evidence of injection drug use but did have evidence of other routes of administration. Among these deaths, snorting (52.4% fentanyl and 68.8% fentanyl analogs) and ingestion (38.2% fentanyl and 29.7% fentanyl analogs) were most common. Although rare, transdermal administration was found among deaths involving fentanyl (1.2%), likely indicating pharmaceutical fentanyl (Table 2). More than one third of deaths had no evidence of route of administration."

Julie K. O’Donnell, PhD; John Halpin, MD; Christine L. Mattson, PhD; Bruce A. Goldberger, PhD; R. Matthew Gladden, PhD. Deaths Involving Fentanyl, Fentanyl Analogs, and U-47700 — 10 States, July–December 2016. Morbidity and Mortality Weekly Report. Vol. 66. Centers for Disease Control. October 27, 2017.

8. Alcohol as a Factor in Overdose Deaths Attributed to Other Drugs in the US

"In 2014, alcohols, including ethanol and isopropyl alcohol, were involved in 15% of all drug overdose deaths and 17% of the drug overdose deaths that mentioned involvement of at least one specific drug. Table E shows the frequency of alcohol involvement among drug overdose deaths involving specific drugs.

"• Alcohol involvement was mentioned in 12%–22% of the drug overdose deaths involving fentanyl, heroin, hydrocodone, morphine, oxycodone, alprazolam, diazepam, or cocaine.

"• Alcohol involvement was mentioned in less than 10% of the drug overdose deaths involving methadone and methamphetamine."

Warner M, Trinidad JP, Bastian BA, et al. Drugs most frequently involved in drug overdose deaths: United States, 2010–2014. National vital statistics reports; vol 65 no 10. Hyattsville, MD: National Center for Health Statistics. 2016, pp. 5-6.

9. Deaths from Drug Overdose in the United States in 2015

"During 2015, drug overdoses accounted for 52,404 U.S. deaths, including 33,091 (63.1%) that involved an opioid. There has been progress in preventing methadone deaths, and death rates declined by 9.1%. However, rates of deaths involving other opioids, specifically heroin and synthetic opioids other than methadone (likely driven primarily by illicitly manufactured fentanyl) (2,3), increased sharply overall and across many states."

Rudd RA, Seth P, David F, Scholl L. Increases in Drug and Opioid-Involved Overdose Deaths — United States, 2010–2015. MMWR Morb Mortal Wkly Rep 2016;65:1445–1452. DOI: dx.doi.org/10.15585/mmwr.mm655051e1

10. Opioid Involvement in Deaths in the US Attributed to Drug Overdose, 2016

According to the US Centers for Disease Control, in 2016, there were 63,632 drug overdose deaths in the United States. The CDC further estimates that of those, 42,249 deaths involved any opioid.

The CDC reports that in 2016, 15,469 deaths involved heroin; 14,487 deaths involved natural and semi-synthetic opioids; 3,373 deaths involved methadone; and 19,413 deaths involved synthetic opioids other than methadone, a category which includes fentanyl. The sum of those numbers is greater than the total opioid involved deaths because, as noted by the CDC, "Deaths involving more than one opioid category (e.g., a death involving both methadone and a natural or semisynthetic opioid such as oxycodone) are counted in both categories."

Hedegaard H, Warner M, Miniño AM. Drug overdose deaths in the United States, 1999–2016. NCHS Data Brief, no 294. Hyattsville, MD: National Center for Health Statistics. 2017.

11. Rise in Opiate Prescriptions in US

"Even though opioids have been controlled in the United States with regulations and restrictions, opioid utilization has been increasing at an unprecedented pace (1-10). Manchikanti et al (1), in an evaluation of opioid usage over a period of 10 years, showed an overall increase of 149% in retail sales of opioids from 1997 to 2007 in the United States, with an increase of 1,293% for methadone, 866% for oxycodone, and 525% for fentanyl. Similarly, the increase in therapeutic opioid use in the United States in milligrams per person from 1997 to 2007 increased 402% overall, with the highest increase in methadone of 1,124% mg/person and oxycodone of 899% mg/person."

Christo,Paul J.; Manchikanti, Laxmaiah; Ruan, Xiulu; Bottros, Michael; Hansen, Hans; Solanki, Daneshvari R.; Jordan, Arthur E.; and Colson, James , "Urine Drug Testing In Chronic Pain," Pain Physician (Paducah, KY: American Society of Interventional Pain Physicians, March/April 2011), Vol. 14, Issue 2.

12. Synthetic Opioids, Including Fentanyl

"With a total of 38 different opioids reported, the number of synthetic opioids has grown rapidly in Europe since the first substance was reported in 2009. In fact, most of these substances have been reported for the first time during the past two years, with 9 reported in 2016 and 13 during 2017. Although they play a small overall role in Europe’s drug market, many of the new opioids are highly potent substances that pose a risk of life-threatening poisoning because an overdose can cause respiratory depression (slowing down of breathing), which can lead to respiratory arrest (stopping breathing) and death. The public health importance of this risk is reflected in the fact that most deaths involving illicit opioid use are caused by respiratory depression (White and Irvine, 1999). Of particular concern are the new fentanils. These substances currently dominate this group, with a total of 28 reported since they first appeared in 2012.

"Reflecting their small share of the market as well as their high potency, new opioids accounted for only around 2% of the total number of seizures of new substances and about 0.2% of the total quantity reported to the EU Early Warning System during 2016. New opioids are found mainly in powders but also in tablets and, since 2014, liquids. For the most part, seizures are dominated by fentanils. There were around 1,600 seizures of new opioids reported by law enforcement during 2016, of which 70% were related to fentanils. These included 7.7 kg of powders (of which 60% contained fentanils), approximately 23,000 tablets (of which 13% contained fentanils) and 4.5 litres of liquids (of which fentanils accounted for 96% of the total). Some of these liquids are from seizures made by police and customs of nasal sprays, which appear to be growing in popularity as a way of using these substances."

European Monitoring Centre for Drugs and Drug Addiction (2018), Fentanils and synthetic cannabinoids: driving greater complexity into the drug situation. An update from the EU Early Warning System (June 2018), Publications Office of the European Union, Luxembourg.

13. Growth of Fentanyl on the Illegal Market

"Alongside their legitimate uses as medicines and in research, the fentanils also have a long history of illicit use as replacements for heroin and other controlled opioids. Between 1979 and 1988, more than 10 fentanils that had been made in illicit laboratories were detected on the drug market in the United States (Henderson, 1991). The first was alpha-methylfentanyl, followed by substances such as 3-methylfentanyl and 4-fluorofentanyl. Typically, they were sold as heroin or ‘synthetic heroin’. Together, these substances were involved in more than 100 deaths, mostly in the state of California. Later, in the mid-2000s, illicitly manufactured fentanyl was sold as heroin or in mixtures with heroin, and was responsible for outbreaks of overdoses that involved hundreds of deaths in the eastern United States (Schumann et al., 2008). It appears that, with the exception of Estonia, where 3-methylfentanyl and fentanyl were responsible for an epidemic of fatal poisonings during this time, these substances caused limited problems elsewhere in Europe (Berens et al., 1996; de Boer et al., 2003; Fritschi and Klein, 1995; Kronstrand et al., 1997; Ojanperä et al., 2008; Poortman-van der Meer and Huizer, 1996).

"Over the past few years, there has been a large increase in the availability of fentanils in the United States, Canada and Europe (Gladden et al., 2016; US CDC, 2015). This has been driven by the opioid epidemics in North America, interest in selling these substances in Europe and broader changes in the illicit drug market."

European Monitoring Centre for Drugs and Drug Addiction (2018), Fentanils and synthetic cannabinoids: driving greater complexity into the drug situation. An update from the EU Early Warning System (June 2018), Publications Office of the European Union, Luxembourg.

14. Fentanyl in the Context of New Psychoactive Substances

"Since 2012, a total of 28 new fentanils have been identified on Europe’s drug market. This includes eight substances that were reported for the first time in 2016 and 10 during 2017. During this period, there has also been a large increase in seizures reported by customs at international borders and police at street-level (Figure 4) (see also ‘Reducing the risk of occupational exposure to fentanils’, page 11). While the picture differs widely across Europe, 23 countries have reported detections of one or more of these substances (Figure 5) (2). Reports to the EMCDDA of fatal poisonings have also increased substantially from some countries (EMCDDA, 2016a; EMCDDA, 2017a,b,c,d,e,f,g; EMCDDA, 2018a,b).

"It appears that most shipments of new fentanils coming into Europe originate from companies based in China. Production in illicit laboratories, including in Europe, has also been reported occasionally. Typically, production of fentanyl and other fentanils is relatively straightforward, which adds to the challenges in responding to these substances.

"Like other new substances, one of the reasons behind the increase in these fentanils is that they are not controlled under the United Nations drug control conventions. This means that in many countries they can be manufactured and traded relatively freely and openly — a situation which has been exploited by entrepreneurs and crime groups using companies based in China to make the substances. The fentanils are typically shipped to Europe by express mail services and courier services. From here, they are then sold as ‘legal’ replacements for illicit opioids on the surface web and on the darknet. Unknown to users, they are also sold as heroin or mixed with heroin and other illicit opioids. Occasionally they have also been used to make fake medicines and, less commonly, sold as cocaine (see ‘Fentanils in fake medicines and cocaine’, page 12).

"Fentanils have been found in a variety of physical and dosage forms in Europe. The most common form is powders, but they have also been detected in liquids and tablets. Depending on the circumstances, seizures of powders have ranged from milligram to kilogram quantities. They may be relatively pure, especially when seized coming into the European Union. They may also be mixed with one or more substances. In the latter case, these include commonly used cutting agents (such as mannitol, lactose and paracetamol), as well as heroin and other fentanils/opioids. To a much smaller degree, other drugs, such as cocaine and other stimulants, have also been detected in mixtures with fentanils in Europe. During 2016, more than 4.6 kg of powder containing fentanils was reported, while almost 4.5 litres of liquid and around 2 900 tablets were also reported. Less commonly, fentanils have also been found in blotters and plant material. In these cases, there may be no indication that they contain fentanils, which could pose a risk of poisoning to people who use them."

European Monitoring Centre for Drugs and Drug Addiction (2018), Fentanils and synthetic cannabinoids: driving greater complexity into the drug situation. An update from the EU Early Warning System (June 2018), Publications Office of the European Union, Luxembourg.

15. Worldwide Growth in Novel Psychoactive Substances 2008-2015

"Between 2008 and 2015, a total of 644 NPS had been reported by 102 countries and territories to the UNODC early warning advisory on NPS. The emergence of NPS was reported for the first time in 2015 in Kyrgyzstan and Mauritius. In 2015, the early warning advisory also registered the emergence of NPS in previous years in Belarus, Serbia, South Africa and Tajikistan. The majority of countries and territories that reported the emergence of NPS up to December 2015 were from Europe (41), followed by Asia (30), Africa (16), the Americas (13) and Oceania (2).

"The NPS market continues to be characterized by a large number of new substances being reported. Although data collection for 2015 is still in progress, 75 new substances have been reported to UNODC for the first time, compared with a total of only 66 in 2014. Between 2012 and 2014, most substances reported for the first time belonged to the group of synthetic cannabinoids. The data reported for 2015 so far show a different pattern: first, 20 synthetic cathinones (a group of substances with stimulant effects similar to cocaine or methamphetamine) were reported for the first time — almost as many as synthetic cannabinoids (21); and second, 21 'other substances' (substances not belonging to any of the major groups identified in previous years) were reported for the first time, including synthetic opioids (e.g. fentanyl derivatives) and sedatives (e.g. benzodiazepines).

"A growing number of NPS are reported every year by a large number of countries and territories throughout the world. NPS that have an established presence in the market include ketamine (reported by 62 countries and territories), khat (reported by 56), JWH-018 (reported by 50), mephedrone (reported by 49) and methylone (reported by 47).227 Other NPS are transient in nature and are only reported by a small number of countries and territories for a couple of years."

United Nations Office on Drugs and Crime. World Drug Report 2016. United Nations publication, Sales No. E.16.XI.7.