Recent mortality data in Massachusetts (MA) and other overdose hotspots show an increase in fatal overdoses involving synthetic opioids and cocaine (powdered or crack).^1-5 These overdose deaths are largely driven by fentanyl, which has proliferated the drug market,^1,6-9 and is highly lethal in small doses.¹⁰ Indeed, starting in 2014 through 2017, fatal overdose data from MA shows that the percentage of death involving heroin, prescription opioids, and benzodiazepines has decreased, whereas the percentage of deaths involving cocaine and fentanyl have steadily increased (2014: fentanyl: 42%; heroin: ~64%; prescription opioids: ~27%; cocaine: ~32%; benzodiazepines: ~65%; 2017: fentanyl: 81%; heroin: 39%; prescription opioids: 15%; cocaine: 42%; benzodiazepines: 57%).⁴ While medical and non-medical use of benzodiazepines is common among individuals with opioid use disorder,^11,12 the increase in postmortem toxicology reports involving both fentanyl and cocaine in particular raise questions about how fentanyl and cocaine are being used and whether people who use drugs are aware of fentanyl in the drug supply.^13-15

While valuable, postmortem toxicology data do not provide information on how deceased individuals use drugs and whether their consumption of one or more drugs was intentional.¹³ Research on the intentional, concurrent use of cocaine and heroin⁸ finds that many individuals combine cocaine and heroin simultaneously or sequentially.^16-18 Indeed, people who use “speedballs” combine cocaine and opioids in a single injection.¹⁹ Some individuals may also use cocaine and opioids at different times of the day.^16,17 Other people, however, exclusively use opioids or exclusively use cocaine.^16,20 While these documented patterns of heroin and cocaine use are informative, they do not speak to how individuals consume fentanyl (i.e. through purposeful use vs. unintentional consumption). Given the impossibility of surveying and interviewing deceased individuals about their intended or unintentional use of fentanyl and cocaine prior to overdosing, it is important to conduct research with people with variable patterns of cocaine and/or opioid use to understand the mechanisms through which fentanyl is consumed and may increase the risk for fatal and nonfatal overdose.

While co-use of substances may be intentional, the cooccurrence of cocaine and fentanyl in the drug supply is increasing and may result in unintentional use.^21-28 Indeed, drug seizure data and surveillance research find that cocaine is being intentionally cut with and/or accidentally adulterated with fentanyl resulting in the unintentional consumption of fentanyl.^7,9,27 Studies have documented that communities of people who primarily use heroin are highly aware of fentanyl contamination in the heroin supply and have community standards and practices in place to prevent fatal overdoses.²⁹ Limited evidence, on the other hand, suggests that people who do not use opioids or who use opioids other than heroin, such as prescription pain pills, are less informed about overdose risks;³⁰ no research to our knowledge has documented awareness of fentanyl contamination and perceived risk of opioid overdose as a result of contamination.

Also understudied is the extent to which individuals who primarily use cocaine are prepared to respond to an opioid overdose, which is an important line of inquiry in light of increasing contamination of fentanyl in the cocaine supply. To that end, the prevention of fatal opioid-related overdoses requires that those witnessing an overdose know how to recognize and respond to an overdose event. Moreover, once a bystander recognizes that a person is overdosing, they must act quickly to prevent it from turning fatal.³¹ The best available tool to prevent a fatal overdose is to administer the opioid-overdose reversal drug naloxone (brand name Narcan). While the widespread availability of naloxone can reduce fatal overdoses, naloxone is only effective if people are aware of it, have it on them or can quickly acquire it, and know how to administer it within a time window where it can be effective.^32,33 Compared to people who exclusively use cocaine, individuals with a history of opioid use may be better able to recognize an opioid-involved overdose as they are likely to have witnessed or personally experienced an overdose.^34,35 Research also finds high levels of naloxone awareness and moderate levels of training among people who use opioids,^36,37 but access to naloxone can vary widely according to geographic location, legal restrictions, and implementation model.^37-39 However, no research, to our knowledge has explored naloxone awareness, use, and accessibility among people who use cocaine and have no history of opioid use.

Given the gaps in the extant literature, the current study sought to use quantitative and qualitative methods to examine overdose risk and preparedness to respond to an overdose among people who use cocaine and have no history of opioid use relative to those with an opioid use history. Findings from this study can inform overdose prevention efforts to reduce the incidence of overdose among people who use cocaine and other drugs.

Between August 2017 and November 2019, we conducted a mixed-methods rapid assessment of consumer knowledge with 469 people who use drugs in Massachusetts. Individuals were eligible for the study if they were 18 years of age or older; a resident of Massachusetts; and reported using an illicit drug in the past 30 days. Individuals who used marijuana or alcohol alone were not eligible as both are legal in the state of Massachusetts. Individuals who did not report cocaine or opioid use in the past 30 days were excluded from this analysis.

This is the first study, to our knowledge, to use mixed methods to explore indicators of opioid overdose risk and overdose response preparedness by patterns of cocaine and/or opioid use. Findings showed that, relative to those who have a past or current history of opioid use, participants who use cocaine and have no history of opioid use are more likely to be unaware of fentanyl in the drug supply; are less likely to know how to recognize an opioid overdose; and are less prepared to respond to an overdose. These findings help generate hypotheses about what is contributing to the increasing trend in fentanyl and cocaine positive toxicology results among people who experienced nonfatal⁴⁵ and fatal overdoses^1,3,13 in recent years. Based on the findings from this study, we theorize that individuals who unintentionally consume fentanyl-contaminated cocaine and are unaware of fentanyl in the drug supply are at much greater risk for personally experiencing a fentanyl overdose and less prepared to respond to a witnessed overdose than individuals who have a past or current history of opioid use. These findings extend prior research on overdose risk and preparedness among people who use drugs^33,46-48 and underscore the need for public health intervention strategies to increase awareness of fentanyl contamination in the drug supply and access to and uptake of harm reduction strategies to prevent fatal fentanyl overdoses among people who use cocaine and other drugs.

Despite high fentanyl awareness overall, a lower proportion of participants in the present study knew of or suspected that fentanyl was in the drug supply, with significant differences observed according to substance use history. Indeed, 92% of participants who used cocaine and had no history of opioid use reported that they did not believe fentanyl was in their drugs whereas most of those (>82%) who were currently using opioids believed fentanyl was in their drugs. Qualitative interviews supported these findings as many participants who had no history of opioid use indicated that they did not believe that their drugs ever contained fentanyl. Research finds that individuals who do not use opioids are at elevated risk of fatal opioid overdose due to a lack of tolerance to opioids.² Given evidence of ongoing fentanyl contamination of the cocaine supply,^1,3,9,13 lack of awareness of fentanyl in the drug supply has the potential to be particularly lethal for individuals who unintentionally consume fentanyl-contaminated cocaine.

The small subset of participants who only used cocaine and who were aware that the drug supply was contaminated with fentanyl had predominately learned about possible contamination from their drug use network, a finding which aligns with previous research which showed that individuals who use drugs often acquire information about drug safety through their drug use network.³⁰ Conversely, and consistent with prior research,^49,50 people who had a current or past history of opioid use tended to learn about fentanyl in the drug supply through their own use experiences or in the context of receiving treatment for substance use disorder. These findings add to the literature by showing significant gaps in awareness of fentanyl in the drug supply among people who do not intentionally use opioids and underscore the need to increase awareness about fentanyl in the drug supply, particularly among those with no history of intentional opioid use in order to prevent fatal opioid-involved overdoses.

In addition to being less aware of fentanyl in the drug supply, individuals who used cocaine in our sample and did not have a history of opioid use were less able to recognize the signs and symptoms of an opioid overdose, relative to individuals who were actively using or who had previously used opioids. Among the small subset of participants who had personally experienced an overdose and had no history of opioid use, only a few attributed the overdose to fentanyl, whereas the majority of those with a past or current history of opioid use attributed their overdose experiences to fentanyl. Similarly, those who were actively using opioids reported significantly more experiences of having witnessed an overdose than those without a history of opioid use. Moreover, our qualitative data demonstrated that, relative to people with no opioid use history, individuals who had personally experienced an overdose or witnessed other people overdosing could clearly describe the signs and symptoms of an opioid overdose and knew when medical intervention was necessary. Notably, however, there were a few outliers who had no opioid use history but knew how to respond to an overdose based on witnessing the experiences of family members or friends living with opioid use disorder. These findings extend prior qualitative research describing the ability of people who intentionally use opioids to recognize an overdose³² and emphasize the importance of training all people to know how to recognize an overdose regardless of whether they use opioids themselves.

The present study also found that participants who used cocaine and did not have a history of opioid use were less prepared to respond to an opioid overdose, relative to individuals with current or past opioid use. In fact, although awareness of naloxone was high among the full sample (97.2%), only 62.6% carried naloxone on them. Based on a long-standing, state-wide community naloxone distribution program in Massachusetts, it may not be surprising that both awareness and possession of naloxone were higher among this sample than in other studies of people who use drugs.⁵¹ Still, we detected notable differences according to substance use history. Indeed, the majority of those with a past or current history of opioid use carried naloxone, whereas less than a quarter of those without an opioid use history had a naloxone kit on them or at the place where they use drugs. Further, our qualitative findings indicated that most of the participants who did not carry naloxone made the conscious decision not to carry it because they only used cocaine and did not believe they were at risk of experiencing an opioid overdose. Still, the majority of participants who had witnessed an overdose, used cocaine, and did (72.7%) and did not (69.0%) have a history of opioid use reported that naloxone was given at the last overdose, suggesting that while these individuals may be less equipped to personally administer naloxone, there was someone nearby and/or first responders arrived on the scene early enough to administer naloxone. Nonetheless, there is still room for improvement as more than a quarter of these participants indicated that naloxone was not administered or they did not know whether it was administered at the last overdose they witnessed. Notably, participants who use cocaine, regardless of their opioid use history, saw the value of carrying naloxone - not only so it was on hand for someone else to administer to them if they were to overdose, but also, as more commonly noted, to allow them to intervene and save the life of another person overdosing. Extending prior research among people who use drugs in the U.S.,^48,51-53 this sense of altruism and the willingness to carry naloxone should be leveraged in future efforts to ensure the widespread possession of this lifesaving medication among all people, regardless of their personal use of or proximity to people who use opioids.

Though carrying naloxone is a necessity for being able to properly respond to an overdose, knowing how to properly administer it and having the self-efficacy to do so can be the difference between a fatal vs. non-fatal overdose.^32,33,53,54 Notably, greater than 68% of our participants with a past or current history of opioid use had been trained to use naloxone, whereas only about two-fifths of those who used cocaine and had no known opioid use history were trained. Extending prior research among people who use illicit opioids in Rhode Island,⁴⁸ findings from the present study found that the majority of those who had witnessed an overdose, independent of substance use history, had personally provided or observed naloxone being provided to an overdose victim. Further, our qualitative data showed that those with an opioid use history reported routinely, quickly, and easily responding to a person experiencing an overdose by administering naloxone, whereas those without an opioid use history, tended to report uncertainty about how to administer naloxone and in some cases reported an unwillingness to do so out of fear that they could do more harm. Interestingly, however, those with a current or past history of opioid use less frequently indicated that 911 was called at the last overdose witnessed, relative to those without an opioid use history. Our qualitative data suggest that individuals without an opioid use history may be more likely than those with an opioid use history to call 911 because they do not have naloxone available or recognize that they lack the training to properly intervene as a first responder. While 911 should be called regardless of whether one is able to administer naloxone to a person who is overdosing, not having naloxone available or administering it incorrectly could increase the risk that an individual who is overdosing dies before emergency personnel can arrive on the scene.^32,33,53,54 These findings highlight the importance of having access to naloxone and being trained to use it to prevent a fatal overdose, particularly among those who use cocaine and have no history of opioid use.

Interventions are warranted to help prevent fatal overdoses among people who use cocaine and have not used opioids and/or do not have social networks comprised of people who use opioids. While campaigns to educate people about the potential for fentanyl contamination in the cocaine supply are vital, as noted by participants, this information is routinely disseminated in treatment facilities and syringe service programs. However, individuals who only use cocaine access drug treatment services⁵⁵ and harm reduction programs⁵² at lower rates than those who use opioids. Thus, there is a need for campaigns that reach the broader public, outside of treatment settings, through such pathways as billboards, TV, and web-based advertisements. Such tactics have been used in other areas of the U.S., such as Ohio,⁵⁶ and should be brought to Massachusetts and other overdose hotspots. Further, while knowledge of the potential risk of fentanyl exposure through the use of contaminated cocaine is essential, individuals who use cocaine require harm reduction strategies that can help them mitigate the risk of a fatal fentanyl overdose. Such strategies might include providing people who do not use opioids and their dealers with fentanyl test strips so they can identify the presence of fentanyl in their cocaine and potentially implement harm reduction practices.⁵⁷ All people who use drugs could also benefit from access to drug checking services,^58-60 which provide insight into the presence of all active drugs, including fentanyl and its many analogs, as well as the relative quantity of fentanyl in one’s drugs. Our team has recently initiated a program to embed drug checking capabilities within several harm reduction organizations in Massachusetts, with the long-term goal of using the technology to provide individuals who use drugs with information about the substances they are consuming so that they can implement appropriate harm reduction strategies to mitigate their risk of overdose (https://heller.brandeis.edu/opioid-policy/). Continued efforts must also be made to increase the distribution of naloxone and train more people in overdose prevention preparedness, including naloxone administration, regardless of their substance use history. Findings from our study suggest a willingness on the part of individuals who use drugs to administer naloxone in order to save a life; these altruistic attitudes can and should be leveraged among all residents of Massachusetts in order to reduce the risk of fatal overdose among people who intentionally and unintentionally consume fentanyl.

Several methodological limitations should be considered in light of our findings. Given that we conducted a cross-sectional study, causality cannot be inferred. Additionally, we explored the experiences of people who used drugs in Massachusetts, including those living in high-risk areas and among members of subpopulations at greater risk for fatal opioid overdoses (e.g. Hispanic populations); thus, our findings may not be generalizable to individuals living in other regions of the U.S. or from lower-risk populations. Although we utilized convenience sampling for all sites, our use of RDS in New Bedford and purposive sampling in all other locations may have introduced sampling bias. Additionally, we did not assess lifetime opioid use and had to rely on qualitative interviews and quantitative indicators of opioid use history (e.g. past methadone use); thus, it is possible that misclassification occurred and the true proportion of those without an opioid use history was lower than reported. Additionally, some of our drug use categories relied on relatively small sample sizes; thus, we did not have the power to examine risk factors using adjusted multivariable models. However, common to rapid assessment, these descriptive findings are intended to be preliminary and serve as a starting point for future research. Finally, we tended to recruit individuals living with more advanced substance use disorders as well as low-income, marginally-housed people. Future research should aim to recruit a larger sample of higher income, stably-housed individuals who recreationally use cocaine as these individuals may be even less aware of fentanyl in the drug supply, less equipped to respond to an opioid overdose, and thus at even greater risk of a fatal overdose relative to participants in the present study.

Through our novel mixed-methods study, we documented the limited awareness of fentanyl in the drug supply and the limited ability to respond to an opioid overdose among people who use cocaine and who do not intentionally consume opioids. Public education and health promotion campaigns are needed to increase awareness about fentanyl in the drug supply among people who use cocaine and do not use opioids. Additionally, harm reduction tools such as fentanyl test strips, drug checking services, naloxone, and overdose prevention trainings must be made widely available to all people at risk of consuming lethal doses of fentanyl or who may come into contact with someone experiencing an overdose in order to reduce the incidence of fatal overdoses among people who use cocaine and other drugs in Massachusetts.