Fentanyl, Carfentanyl, and Synthetic Opioids

"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."

"Inhalation is an exposure route of concern if drug particles are suspended in the air. Fentanyl has potentially high bioavailability (12–100%) by inhalation [14, 15]. It is highly suspected that a weaponized aerosolized containing carfentanil and remifentanil were used to subdue hostage-takers of a Moscow theater in 2002. One hundred twenty-five died as a result of this weaponized aerosolized exposure [16]. Although an optimized airborne dispersal device is unlikely to be encountered in a local event, we considered such a scenario for respiratory protection.

"Industrial producers of fentanyl use time-weighted average occupational exposure limits (OEL-TWA) for alfentanil (1 mcg/m3), fentanyl (0.1 mcg/m3), and sufentanil (0.032 mcg/m3) to limit exposure [17]. At the highest airborne concentration encountered by workers, an unprotected individual would require nearly 200 min of exposure to reach a dose of 100 mcg of fentanyl.

"The vapor pressure of fentanyl is very low (4.6 × 10-6 Pa) suggesting that evaporation of standing product into a gaseous phase is not a practical concern [18]."

"Among people aged 12 or older in 2023, 0.3 percent (or 828,000 people) misused fentanyl in the past year, including 0.2 percent of adolescents aged 12 to 17, 0.3 percent of young adults aged 18 to 25, and 0.3 percent of adults aged 26 or older (Table A.12B). Corresponding estimated numbers of people who misused fentanyl in the past year were 50,000 adolescents aged 12 to 17, 110,000 young adults aged 18 to 25, and 668,000 adults aged 26 or older.

"Among people in 2023 who misused any prescription pain reliever in the past year, only 7.4 percent misused fentanyl. Among people who used fentanyl for any reason in the past year, 28.6 percent misused it and 71.4 percent did not.24

"IMF [Illegally Made Fentanyl] Use

"Because people who used IMF may have been unaware that they used it, caution must be taken in interpreting estimates of IMF use; these estimates are almost certainly an underestimate of true IMF use.

"Among people aged 12 or older in 2023, 0.2 percent (or 627,000 people) used IMF in the past year, including 0.1 percent of adolescents aged 12 to 17, 0.2 percent of young adults aged 18 to 25, and 0.2 percent of adults aged 26 or older (Table A.12B). Corresponding estimated numbers of people who used IMF in the past year were 36,000 adolescents aged 12 to 17, 78,000 young adults aged 18 to 25, and 513,000 adults aged 26 or older."

"Historically, there have been a number of US overdose events where a fentanyl was implicated [14▪▪,15▪]. However, the wave of overdose deaths attributed to illicit fentanyls since 2013 is unprecedented. The current rise of fentanyls is considered a positive supply shock, i.e., a supply driven more than demand-driven event [16]. Evidence for this includes: fentanyls are generally sold as ‘heroin’ i.e., fentanyl-adulterated or substituted heroin (FASH) [17,18]; wholesale distribution of FASH [19] and related overdose is regionally distributed with the Northeast and Midwest most affected followed by the South [20–22]; these are illicit products not diverted pharmaceuticals [19]; early on there was mixed desirability for FASH [17,18,23,24]; and there is market incentive in that dose-for-dose fentanyl is cheaper to produce than heroin [3,25]. The reasons why fentanyls were introduced during the current surge is complex; one argument, based on prior episodes, is that they replace heroin during periods of relative shortage [16,26]. In The Future of Fentanyl and other Synthetic Opioids, Pardo et al. highlight a confluence of supply side factors to explain the rise of fentanyls, e.g., more-efficient synthesis methods, internet communication and commerce, and out-paced regulatory environments in source countries e.g. China [27▪▪].

"The fentanyls problem is spreading. Globally, fentanyls have been detected or implicated in deaths in Europe, esp. Estonia, Latvia, and Sweden [27▪▪]. Canada has been particularly hard hit by fentanyl-related overdose [28]. The spread of fentanyls is also happening in the USA. From 2014 to 2017, the fentanyls problem was initially regionally isolated to the US Northeast and Midwest, followed to a lesser degree in the South [20,22]. However, from 2017 to 2018 the region that had the highest relative change in overdose rates due to synthetic opioids was the West [5▪]. Examining CDC data, Shover and colleagues found the share of US synthetic opioid overdose deaths attributable to seven western jurisdictions more than tripled from 2017 to 2019 [29▪▪]. Supply side data also support increasing fentanyls supply, esp. in the form of counterfeit pills, to the West [30]. And the supply is diversifying from China and Mexico to include India as a source country [31▪]."

"Findings

"The percent of US overdose deaths involving both fentanyl and stimulants increased from 0.6% (n = 235) in 2010 to 32.3% (34 429) in 2021, with the sharpest rise starting in 2015. In 2010, fentanyl was most commonly found alongside prescription opioids, benzodiazepines, and alcohol. In the Northeast this shifted to heroin-fentanyl co-involvement in the mid-2010s, and nearly universally to cocaine-fentanyl co-involvement by 2021. Universally in the West, and in the majority of states in the South and Midwest, methamphetamine-fentanyl co-involvement predominated by 2021. The proportion of stimulant involvement in fentanyl-involved overdose deaths rose in virtually every state 2015–2021. Intersectional group analysis reveals particularly high rates for older Black and African American individuals living in the West.

"Conclusions

"By 2021 stimulants were the most common drug class found in fentanyl-involved overdoses in every state in the US. The rise of deaths involving cocaine and methamphetamine must be understood in the context of a drug market dominated by illicit fentanyls, which have made polysubstance use more sought-after and commonplace. The widespread concurrent use of fentanyl and stimulants, as well as other polysubstance formulations, presents novel health risks and public health challenges."

"The number of opioid NPS found on markets worldwide grew from just one substance in 2009 to 14 in 2015, 56 in 2019 and 87 in 2020,²⁰ by which time synthetic opioids had become the third most numerous group of NPS in terms of the number of different substances reported by Member States in 2020 (after NPS stimulants and NPS cannabinoid receptor agonists and slightly ahead of NPS hallucinogens).²¹ Synthetic opioids accounted for the highest number of NPS identified for the first time at global level in 2020, with 22 new substances (29 per cent of those identified), including both fentanyl analogues and other opioids. Although fentanyl has been under international control since 1964 and a number of fentanyl analogue medicaments were scheduled in the 1980s (sufentanil, alfentanil and 3-methylfentanyl) and in the 1990s (thiofentanyl and remifentanil), a far larger number of fentanyl-type NPS (i.e. fentanyl analogues without any recognized medical use) emerged in the 2010s.²²

"The number of NPS categorized as “other substances” has also continued to grow. "Other substances" include synthetic NPS that do not belong to a precise category, in particular NPS with sedative and hypnotic effects, most of which are benzodiazepine-type NPS.²³ Benzodiazepine-type NPS are often sold at very low prices, sometimes in packages mimicking existing medicines, have varying dosages of active ingredients and contain contaminants, including highly potent synthetic opioids.²⁴

"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."

"Fentanyl is amenable to transdermal absorption because of its low molecular weight and lipophilicity [19, 20]. Depending on the specific product, transdermal delivery systems (“patches”) take 3–13 h to produce a therapeutic serum fentanyl concentration and 35 h to reach peak concentration [21–24]. Absorption of liquid or aqueous fentanyl increases with larger surface area of application, duration of application, broken skin, and heat. The physical properties of fentanyl analogs are similar to fentanyl, suggesting potential for dermal absorption. In a small volunteer study, sufentanil citrate applied to the forearm and covered in an occlusive dressing was absorbed comparably to fentanyl, although exact bioavailability was not determined [25].

"However, incidental dermal absorption is unlikely to cause opioid toxicity. If bilateral palmar surfaces were covered with fentanyl patches, it would take approximately 14 min to receive 100 mcg of fentanyl [using a body surface area of 17,000 cm2, palm surface area of 0.5% [26], and fentanyl absorption of 2.5 mcg/cm2/h [24]. This extreme example illustrates that even a high dose of fentanyl prepared for transdermal administration cannot rapidly deliver a high dose.

"The above calculation is based on fentanyl patch data, which overestimates the potential exposure from drug in tablet or powder form in several ways. Drug must have sufficient surface area and moisture to be efficiently absorbed. Medicinal transdermal fentanyl utilizes a matrix designed to optimize delivery, whereas tablets and powder require dissolution for absorption. Relatedly, powdered drug sits on the skin, whereas patches have adhesive to hold drug in close proximity to the skin allowing both to remain moist. Finally, in the above quoted figure, 2.5 mcg/cm2/h represents delivery at steady state after drug has penetrated the dermis, which overestimates the amount of absorption in the first few minutes of dermal exposure. This initial period is of most relevance in unintentional exposure, because fentanyl that is observed on skin can be rapidly removed by mechanical (brushing) means or cleansing with water. Therefore, based on our current understanding of the absorption of fentanyl and its analogs, it is very unlikely that small, unintentional skin exposures to tablets or powder would cause significant opioid toxicity, and if toxicity were to occur it would not develop rapidly, allowing time for removal."

"With the relatively recent surge in fentanyl-related overdoses, a new occupational safety concern has emerged among emergency responders: the fear of overdosing from touching fentanyl [8]. In 2017 alone, over 150 media reports describing first responder exposures to opioids surfaced [9]. Reports of overdose due to fentanyl contact among first responders [10–13] have been repeatedly refuted by medical experts [14–16]. Yet, mixed messages from the US government agencies [17] and their prominence in media outlets have catalyzed the spread of misinformation about the risks of accidental fentanyl contact. The high level of concern about this theoretical threat has been especially stark in the context of the COVID-19 pandemic, particularly in the USA, when police have reportedly expressed comparatively little anxiety about contracting the potentially deadly virus [18].

"There has been an increase in products marketed to address the fear of fentanyl, including fentanyl exposure prevention kits [19, 20], gloves marketed to protect against fentanyl [21], other fentanyl-resistant gear and screening devices [22], and fentanyl clean-ups [23]. Additionally, legislators in the USA have proposed the Providing Officers with Electronic Resources (POWER) Act that would fund state and local enforcement agencies to purchase fentanyl screening devices to protect officers from incidental exposure [24]. However, because these screening procedures require the use of class B hazmat suits [25] and other equipment prior to responding to the overdose, these precautions could potentially delay the time-sensitive, lifesaving administration of naloxone and rescue breathing."

"Fentanyl test strips (FTS) emerged in this context as a drug checking tool to address the burgeoning fentanyl crisis. FTS was originally developed as a field immunoassay to screen for the presence of fentanyl in urine, but harm reduction organizations discovered that FTS can also detect fentanyl in illicit drug solutions. This realization has led many harm reduction organizations to distribute FTS to people who consume street opioids as an off-label approach to test street drugs for fentanyl (Peiper et al., 2019). Research published during this early period exposed a growing concern of unwitting fentanyl exposure among heroin consumers and a general willingness to use FTS. Studies showed a high percentage of PWID were interested in using FTS to test heroin (Allen et al., 2020; Krieger, Goedel, et al., 2018; Park et al., 2021; Sherman et al., 2019) and syringe services programs were making them increasingly available alongside naloxone in OD prevention kits (Beharie et al., 2023).

"Of particular significance were a handful of studies showing PWID modifying their drug use behavior upon receiving positive FTS results (Goodman-Meza et al., 2022; Krieger, Goedel, et al., 2018; Peiper et al., 2019). Notably, a community-based study in North Carolina found that PWID with positive FTS results had 5 times higher odds of practicing safer drug use compared to PWID with negative results (Peiper et al., 2019). Similar studies arrived at comparable effects and together confirmed that PWID were willing to use FTS and initiate risk reduction behaviors when consuming fentanyl (Park et al., 2020, 2021)."

"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."

"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%)."

"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 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."

"Concerns about fentanyl exposure continue to spread despite a clear consensus from medical experts that overdose from incidental skin contact is a medical impossibility [14, 15]. Indeed, this claim has been officially debunked by the American College of Medical Toxicology and the American Academy of Clinical Toxicology [16] and the National Occupational Safety and Health with the CDC [26]. A drug policy advocate has also disproven this myth by holding fentanyl powder in his hand without consequence and widely circulating the internet footage [15]. Researchers who study reported overdoses from fentanyl exposure among emergency responders have explained that cases documented thus far can best be attributed to the “nocebo effect”—a phenomenon in which individuals believe they have encountered a toxic substance and therefore experience the expected symptoms of exposure [27]. This is consistent with our broader understanding of occupational wellness and mental health—or lack thereof—among first responders [28]. When individuals are already operating under acute stress and with few mental health reserves, fear of overdose from touching fentanyl could serve as an additional stressor."

"Importantly, our results show that evidence of injection was more prevalent among decedents with xylazine and heroin and/or fentanyl detections. Despite limited literature on the health effects of chronic xylazine use, regular injection of xylazine has been associated with skin ulcers, abscesses and lesions in Puerto Rico.^{2 3} Semistructured interviews with people who use xylazine in Puerto Rico revealed that regular use of xylazine leads to skin ulcers.⁴ As skin ulcers are painful, people may continually inject at the site of the ulcer to alleviate the pain as xylazine is a potent α2-adrenergic agonist that mediates via central α2-receptors, which decreases perception of painful stimuli.¹ People may self-treat the wound by draining or lancing it, which can exacerbate negative outcomes.⁸ While Philadelphia has seen a rise in skin and soft tissue infections relating to injection drug use, it is not yet clear whether or not this is due to increased presence of xylazine in the drug supply.⁹"

"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."

"Harms of xylazine use in humans are not well documented, but evidence suggests that combined use of xylazine and an opioid such as fentanyl may increase the risk of overdose fatality.¹ Although naloxone, the opioid overdose reversal drug, is not effective against xylazine alone, unintentional fatal overdoses with xylazine detections also had heroin and/or fentanyl detections in Philadelphia, indicating timely administration of naloxone is critical for preventing deaths. Additional treatment for xylazine poisoning may involve supportive care using intubation, ventilation and administration of intravenous fluid.¹

"Of note, as fentanyl has largely replaced the heroin supply in Philadelphia, xylazine has been increasingly found in combination with fentanyl. Some evidence suggests that the combination of xylazine and fentanyl in humans may potentiate the desired effect of sedation and the adverse effects of respiratory depression, bradycardia and hypotension caused by fentanyl alone,¹ comparable to the synergistic effects of combining benzodiazepines with heroin and/or fentanyl.⁷ While benzodiazepines were detected in 97 (58%) of the 168 unintentional overdose deaths with heroin and/or fentanyl detections in Philadelphia in 2010, this decreased to 232 (28%) of the 858 unintentional overdose deaths with heroin and/or fentanyl detections in 2019. This decline may be the result of increasing demand for xylazine among people who use drugs in Philadelphia and/or changes in the illicit drug market as drug seizure data indicate that xylazine is increasing in polydrug samples. Indeed, focus groups with people who use drugs in Philadelphia have suggested that the addition of xylazine to fentanyl “makes you feel like you’re doing dope (heroin) in the old days (before it was replaced by fentanyl)” when the euphoric effects lasted longer."

"Results from samples expected to be stimulants were divergent between testing groups. Crystal methamphetamine samples tested using take-home drug checking were reported as fentanyl positive more often than on-site samples (27.6% vs. 5.2%). The same pattern was seen for cocaine samples tested using take-home drug checking (17.2% vs. 1.1%). However, the study was underpowered to evaluate equivalence between these testing groups. A small portion of the test strips (3.8%) yielded an unclear or illegible response. It is unclear what the participants did in these cases, but the inclusion of multiple test strips would have allowed for repeat testing.

"Notably, when the results of take-home drug checking were stratified based on previous experience with fentanyl test strips, there was a trend towards a smaller difference between the results of take-home drug checking and on-site drug checking. For opioids, when only results from those who were using fentanyl test strips for the first time were included, there was a difference of 1.6% between take-home drug checking and on-site drug checking. This difference was reduced to 0.6% when only including samples from those who had self-reported prior experience with using fentanyl test strips. Similar results were seen for crystal methamphetamine (28.9% to 15.2%) and cocaine (28.3% to 7.8%)."

"In a harm reduction setting, a FTS might be used to test the drug residue in a cooker or baggie for fentanyl before use of the drug. Our results show that the concentrations of diphenhydramine, methamphetamine, and MDMA commonly found in street drugs are at levels that could generate false positives on the FTS. Many cookers and small baggies hold about 0.75–1 mL of water. If we assume there is 5 mg of methamphetamine in the container that is diluted with 1 mL of water, the concentration of methamphetamine will be 5 mg/mL and would trigger a false positive on the FTS. If the residue were dissolved with 10 mL of water, the methamphetamine concentration would be 0.5 mg/mL and would render a true negative on the FTS. If the drug residue instead consisted of 95% methamphetamine and 5% fentanyl, the 10 mL dilution would ensure that the methamphetamine concentration would not interfere with the FTS while the true positive result would come from the fentanyl present in the sample. As practical guidance for harm reduction groups, a dilution with at least 50 mL of water will provide a good margin of error for accurate detection of fentanyl in cooker or powder residues while avoiding false positives from other drugs. Over dilution is not a likely problem; the FTS is sensitive enough that if there was just 0.5 mg of fentanyl residue in a cooker and it is dissolved in a 10-L bucket of water (50 µg/L or 50 ng/mL), the FTS will still detect the fentanyl present."

"Polysubstance use may increase the risk of opioid overdose [36, 37] but although studies have found associations between overdose and combined use of heroin with other sedatives [38], the literature on overdose risk from heroin-stimulant combinations is limited [19, 39]. Goofball use has been associated with larger networks of PWID [19], which while potentially protective against overdose, may increase the likelihood of sharing injection equipment and contribute to transmission of bloodborne infections. Additionally, participants reported using methamphetamine to alter their sleep schedules or that methamphetamine use kept them awake for days, and the impact of sleep disturbances on susceptibility to opioid overdose needs additional study.

"Consistent with other studies [20], several respondents strongly believed in the ability of methamphetamine to prevent and reverse opioid overdose. Set against this are statistical data that show greater frequency of overdose among individuals co-using methamphetamine and heroin compared to people solely using heroin [19, 40] and rising numbers of deaths involving combinations of fentanyl and methamphetamine [41]. Increased mortality from co-use of these substances could represent greater co-use of methamphetamine overall or escalating fentanyl saturation of the opioid market but does not explain the lay belief in the possible protective effects of methamphetamine against opioid overdose.

"A potential explanation arises from recent mouse-model data which shows a bi-directional effect of amphetamine on fentanyl-depressed respiration depending on amphetamine dosage. Lower amphetamine doses depressed respiration after fentanyl, increasing the likelihood of overdose but higher amphetamine doses elevated respiration [42]. If applicable to humans, this finding may help to explain the apparent contradiction of methamphetamine both increasing and reducing the risks of fatal overdose and could lead to the development of important harm reduction strategies. However, more specific research on this drug interaction in humans is needed to understand this causal pathway.

"The importance of dosage and drug sequence when using methamphetamine to mitigate adverse respiratory effects of opioids, fentanyl in particular, requires further study. Order of use may not be evident in post-mortem toxicology and the interaction of these drug mechanisms over time needs further exploration. Amidst rising amphetamine-related hospitalizations [43, 44], research should also consider other specific morbidity risks posed by co-use of opioids and methamphetamine, including how non-injection modes of use (i.e. smoking, snorting [45]) may impact morbidity and mortality (e.g. by reducing HIV/HCV or overdose risks)."

"Methamphetamine use is increasing in the wake of the opioid crisis in the United States (U.S.). Increases in the use of this highly addictive stimulant have been documented in the health literature^1,2 as well as in the national media.³ In Denver, Colorado, and Seattle, Washington, the increase in methamphetamine use has predominantly involved a growing proportion of people who inject drugs (PWID) using both methamphetamine and heroin, either separately or in a single injection commonly known as a goofball.^1,2 (Goofball can also be smoked.) Data from San Diego, California, and Tijuana, Baja California, Mexico have also demonstrated high levels of co-injection of methamphetamine and heroin.⁴

"Although existing literature provides some insight into the characteristics and circumstances of people who inject goofball, the available data remain very limited. We previously published an analysis of data from syringe services program (SSP) clients in the Seattle area between 2009 and 2017, and found that people who used goofball were significantly more likely than other PWID to be young, homeless, inject daily, and self-report an opioid overdose.² Additional data on specific injection behaviors, other health outcomes, and interest in treatment among people who inject goofball are needed to understand how to most effectively implement harm reduction and substance use treatment efforts. In addition, it is important to focus on people whose primary drug is goofball to determine how the needs of this potentially high acuity group may differ from people predominantly using other drugs."

"Findings from these recent surveys of SSP clients in Seattle showed that goofball use is common, with over half of respondents reporting using heroin and methamphetamine together. Moreover, PWID whose main drug was goofball reported considerable health risks and morbidity, including more frequent injection, femoral and jugular vein injection, public injection, abscesses and skin infections, infected blood clots and blood infections, and endocarditis. They also reported more overdose-related risk including injecting alone and witnessing both opioid and stimulant overdoses. At the same time, the majority of PWID who reported that goofball was their main drug also reported interest in reducing or stopping their drug use. In light of the opioid crisis in the U.S., it is critical for stakeholders to recognize the substantial and growing overlap between opioid and methamphetamine use, acknowledge the contextual factors that may be driving the combined use of these drugs, and develop health interventions accordingly.

"Polysubstance use is a global phenomenon, especially the use of opioids in combination with stimulants, and has been associated with high levels of HIV and other negative health outcomes.^9–11 Prior opioid-stimulant co-use research has mostly focused on speedball. At present, there is limited epidemiologic data on the unique health effects of combined heroin and methamphetamine use. Due to the shorter half-life of heroin relative to methamphetamine,¹² people using goofball may re-dose when the effects of heroin wane but before the effects of methamphetamine have worn off, potentially leading to the unsafe injection behaviors or overdose.

"A very high proportion (82.5%) of people whose main drug was goofball were homeless or unstably housed. This aligns with dramatic increases in homelessness in the Seattle area.¹³ Many other observed associations with goofball use are correlated with homelessness. People living outdoors may use stimulants to counter the depressant effects of opioids to remain more aware of their possessions and surroundings.¹⁴ However, further research is needed to better understand the motivations and causes of the increase in methamphetamine use, particularly among this largely homeless population with high levels of risk and vulnerability."

"The role of co-use of heroin and methamphetamine in overdose requires greater exploration. Intentional co-use of heroin and methamphetamine is increasing in the US, whether in simultaneous injection as a ‘goofball’, sequential injection or other combined modes, including smoking and snorting. Supply changes have played a part in widespread distribution of ‘ice’ or ‘cream’, a more potent and lower price Mexican-sourced methamphetamine supplanting the domestic product [10, 16].

"‘Goofball’ was originally a term for barbiturate-type drugs with the earliest mention in the literature as heroin-methamphetamine injection in 2005 [17]. Heroin and methamphetamine co-use (referred to in some locations as a goofball and in others as a speedball, which historically has been a combination of heroin and cocaine) is spreading in locations as varied as Seattle, Washington; San Diego, California; Denver, Colorado; and Dayton, Ohio [18,19,20,21]. Qualitative research has found many people who use drugs (PWUD) believe methamphetamine can prevent or reverse opioid-related overdoses [20] and reduce withdrawal severity [22]. A study in Vancouver, Canada, found that practitioners used goofballs bi-directionally, both to enhance the individual effects of opioids and methamphetamine and to control for each drug’s negative effects [23]. However, knowledge about forms of co-use of methamphetamine and heroin, particularly from recent years, is needed to understand rising mortality among people using methamphetamine."

"In order to help prevent overdoses, lateral flow immunoassay test strips originally designed for monitoring traces of fentanyl and its analogs in urine are being explored as a drug checking technology in harm reduction contexts [17,18,19,20]. One commonly used fentanyl test strip or “FTS” (BTNX Inc., Markham, ON, Canada) is a lateral flow chromatographic immunoassay for the qualitative detection of fentanyl in urine at the cutoff concentration of 20 ng/mL. A positive result on this test strip gives one line, a negative result gives two lines, and an invalid test gives either no line or no control line [21]. The “off label” use of the FTS in a harm reduction context involves preparation of a solution of the drug to be checked. For example, the residue in a cooker or baggie may be dissolved in a little water and then tested with the FTS. BTNX Inc. provides information about specificity of their test strip response, but for fentanyl 20 ng/mL FTS, the only drugs tested were fentanyl (detected at 20 ng/mL in urine) and norfentanyl (detected at 375 ng/mL in urine). In addition, a suite of pharmaceuticals were found to be non-interfering at levels of 100 ug/mL in a urine matrix [21, 22]. We have found that common stimulants and cutting agents that are often present in illicit drugs can create false positives. The problem arises from the cross-reactivity of the antibody for these other substances [23]. Although the affinity of the antibody for these substances is much lower than for fentanyl, if they are present at sufficiently high concentrations, they can cause a false positive result [24, 25]. As we consider the 4th wave of the pandemic, it can be expected that drug users will need to test stimulants to see if they contain fentanyl."

"Motives for using methamphetamine with heroin/fentanyl can be conceptualized as forming three thematic categories: ‘intrinsic use’, representing the inherent pleasure of the combination or self-medication of particular conditions; ‘opioid assisting use’ in which methamphetamine helped manage existing heroin/fentanyl use and ‘reluctant or indifferent use’. All 30 individuals had some experience using methamphetamine, whether separately or combined with heroin.

"We heard about and witnessed several ways that people used the two drugs, including simultaneous or alternating injections along a temporal spectrum. Daily order of dosing was another important and varied aspect of goofball use, with participants’ strategies dependent upon time of day, activity level, social situations and other factors. Most participants prioritized heroin over methamphetamine due to managing both opioid withdrawal and limited financial resources. Participants generally used the term ‘heroin’ to describe heroin, heroin adulterated with fentanyls and fentanyls without heroin; this language is reproduced in this paper to incorporate both drugs. Participants used the term ‘speedball’ to indicate co-injection of heroin and methamphetamine simultaneously, and generally did not use this term to refer to use separated in either time or mode of use (snorting, smoking). Ratios of heroin to methamphetamine within a speedball varied significantly among participants based on opioid tolerance, social situations and personal preference.

"The co-use of heroin and methamphetamine, known locally as a ‘speedball’, a term used elsewhere to describe a cocktail of heroin and cocaine, gained popularity among our sample within the last several years, and was virtually unknown before approximately 2015. This was despite the earlier presence of domestically produced ‘shake and bake’Footnote1 methamphetamine in the local drug culture, albeit recently less widely available than the newer ice. Heroin was also a latecomer to the area, with evidence suggesting that the local market developed from 2012 onwards [35]. Among participants where the order of drug progression was clear, all had initiated their opioid use with prescription opioid pills, but had transitioned to heroin after the pills became prohibitively expensive and more difficult to obtain."

"Based on our findings, distributed fentanyl test strips would be reliable for the testing of samples identified as opioids and should be more widely distributed. There is growing evidence that fentanyl test strips may help prevent overdose when included with other evidence-based strategies (Peiper, 2019). Other informal techniques such as visual inspection of a substance have been applied by PWUD, but may not be effective in substances that contain traces of fentanyl (Peiper et al., 2019). Our study situated fentanyl test strips within sites that provide naloxone kits, drug use supplies such as syringes, supervised consumption of substances, and drug checking using both test strips and more sophisticated technologies. In contrast to the potential for behaviour change from drug checking results, analysis of several cohort studies within Vancouver during the period of increasing fentanyl contamination in late 2016 showed that a majority of PWUD did not change their drug use behaviours nor translate the knowledge of a changing drug supply to an increased risk of overdose (Brar et al., 2020; Moallef et al., 2019). These findings indicate the need for targeted education and harm reduction interventions for those at risk. Distribution of testing supplies provides an opportunity for further engagement. In BC, an expansion of this pilot program, including continuation at sites included in this evaluation, has occurred to distribute fentanyl test strips labelled with instructions for use. Notably, the described positive behaviour changes rely on an individual possessing knowledge around safer ways to use substances, including knowledge around using a small amount (“test dosing”) and using with others or not alone to avoid overdose and allow for naloxone administration. Furthermore, participants identified using at an OPS/SCS as a potential behaviour, which necessitates that these services exist. Our findings around behaviour change in response to a positive fentanyl result underscore the need for comprehensive harm reduction services and education."

"Globally, community drug checking programs (CDCPs) allow people to submit drug samples for chemical analysis. The results are shared with the donating individual or organization for their health and safety.³,⁴ Data about the samples help drug supply monitoring and constitute a valid, nonduplicative source of information.⁴,⁵ While this strategy is an established harm-reduction tool in Europe,⁴ it is a new endeavor in the United States. Permissions to use federal funds to distribute immunoassay fentanyl test strips (FTS) came in 2021, indicating support for expansion of drug checking to detect fentanyl and raise community awareness of this approach.⁶,⁷

"Determining whether drug samples contain IMF or analogues can help mitigate consumers' risk of overdose and promote safety interventions.⁸–¹³ One study found substantial changes in overdose safety and drug use behaviors following FTS utilization.¹⁴ Our 3-city FORECAST Study found that many people who use drugs (PWUD) do not prefer drugs containing IMF¹³ and 39% employ practices to reduce risk, given unknown drug purity and content,¹⁵ suggesting advantages to disseminating drug checking results and harm-reducing messages.¹⁶ Drug checking with FTS and a handful of comprehensive CDCPs have been implemented in the United States alongside activities such as syringe service programs (SSPs),¹⁷ but no CDCPs operate as both a harm-reduction service and a drug supply monitoring program in the United States, and none globally integrate public safety partnerships or test noncriminal drug samples from police. We describe the approach and initial uptake of a harm-reduction service and public health monitoring tool, the Massachusetts Drug Supply Data Stream (MADDS), a statewide CDCP built upon public health, harm reduction, and public safety partnerships."

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."

"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."

"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."

"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."

"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."

"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."

"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."