Naloxone for heroin, prescription opioid, and illicitly made fentanyl overdoses: Challenges and innovations responding to a dynamic epidemic

Abstract

Community-based overdose prevention programs first emerged in the 1990’s and are now the leading public health intervention for overdose. Key elements of these programs are overdose education and naloxone distribution to people who use opioids and their social networks. We review the evolution of naloxone programming through the heroin overdose era of the 1990’s, the prescription opioid era of the 2000’s, and the current overdose crisis stemming from the synthetic opioid era of illicitly manufactured fentanyl and its analogues in the 2010’s. We present current challenges arising in this new era of synthetic opioids, including variable potency of illicit drugs due to erratic adulteration of the drug supply with synthetic opioids, potentially changing efficacy of standard naloxone formulations for overdose rescue, potentially shorter overdose response time, and reports of fentanyl exposure among people who use drugs but are opioid naïve. Future directions for adapting naloxone programming to the dynamic opioid epidemic are proposed, including scale-up to new venues and social networks, new standards for post-overdose care, expansion of supervised drug consumption services, and integration of novel technologies to detect overdose and deliver naloxone.

Introduction

The groundwork for the public health concept that opioid overdose death is preventable in the setting of illicit opioid use was first laid with research articles published in the 1970s describing the risk factors for opioid overdose (Brecher, 1972, Monforte, 1977). The first community-based overdose prevention programs for people who use opioids emerged in the 1990s (Darke, 2016). The key elements of these programs were the education of people who use opioids about how to reduce their overdose risk and equipping them with naloxone, the antidote to an opioid overdose, so that they could rescue each other. Since then, these programs have expanded substantially in the United States and Canada to become a leading public health intervention for the prevention of overdose mortality (Oluwajenyo Banjo et al., 2014, Wheeler et al., 2015).

These programs have emerged on a backdrop of a dynamic epidemic of opioid use and opioid overdose in the United States and Canada. In the 1990s and 2000s, expansion of the treatment of acute and chronic pain with prescription opioids was associated with concomitant rise in diversion of prescription opioids to the illicit market, opioid use disorders, and opioid overdose deaths (Centers for Disease & Prevention, 2011; Modarai et al., 2013; Piercefield, Archer, Kemp, & Mallonee, 2010; Shah, Lathrop, Reichard, & Landen, 2008). As the connection between increased opioid prescribing and rising overdose deaths were recognized and efforts were made to limit opioid prescriptions, heroin use increased, likely to meet the rising demand for illicit opioids (Rudd, Aleshire, Zibbell, & Gladden, 2016). Along with increased heroin use, the introduction of illicitly manufactured fentanyl and other synthetic opioids into many illicit opioid markets has resulted in an acute surge in overdose deaths in many communities (Peterson et al., 2016, Rudd, Aleshire et al., 2016). These changes have brought challenges and raised new questions about what was previously known regarding overdose and our response to it.

In the late 1990s and early 2000s, when community overdose education and naloxone rescue kits initially emerged among programs serving people who inject drugs (PWID), heroin was the primary opioid involved in overdose events. In the United States and Canada, most naloxone programs were based in syringe needle access programs (SNAPs) that served people who injected heroin. In the 1990s, SNAPs were recognized as an important evidence-based public health strategy to reduce HIV transmission and the medical complications from injection drug use, yet U.S. federal funding ban was not lifted, in part, until January of 2016. While some local and state health departments supported these programs to reduce HIV and hepatitis rates among PWID, many programs relied on volunteers, foundation and individual funding and operate without any support from health departments.

Programs distributing naloxone to PWID through SNAPs first emerged in the U.S. in Chicago in 1996, the Jersey Channel Islands in Europe in 1998, Berlin, Germany, in 1999, and New Mexico, in 2001 (Dettmer, Saunders, & Strang, 2001; Maxwell, Bigg, Stanczykiewicz, & Carlberg-Racich, 2006). Multiple ecological and other observational studies of community naloxone distribution programs demonstrated that PWID can learn overdose prevention and administer naloxone successfully (Doe-Simkins, Walley, Epstein, & Moyer, 2009; Green, Heimer, & Grau, 2008; Seal et al., 2003, Seal et al., 2005; Tobin, Sherman, Beilenson, Welsh, & Latkin, 2009), and suggested potential ancillary benefits such as decreased substance use, social connection, and empowerment (Wagner et al., 2014, Wagner et al., 2010). San Francisco documented a dramatic reduction in heroin overdose mortality in the early 2000s, from approximately 180 heroin overdose deaths per year in the late 1990s to 10–11 per year from 2010 to 2012, although some of that decrease was a result of transitions to prescription opioids (Visconti, Santos, Lemos, Burke, & Coffin, 2015). Scotland's National Naloxone Programme, which started in 2011, was associated with a 36% reduction in the proportion of opioid-related deaths that occurred in the 4 weeks following release from prison (Bird, McAuley, Perry, & Hunter, 2016). Massachusetts demonstrated reduced opioid overdose mortality rates in communities where overdose education and naloxone distribution programs were implemented compared to communities where they were not implemented (Walley, Xuan, et al., 2013). Community overdose education and naloxone rescue programs have expanded substantially since the 1990s and are now present in 30 U.S. states (Wheeler et al., 2015).

Overdose education and naloxone rescue was not the only public health intervention associated with reductions in heroin overdoses. Baltimore documented a reduction in heroin overdose death that was attributed to expansion of methadone and buprenorphine treatment for opioid use disorder (Schwartz et al., 2013). Vancouver, Canada, responding to a dual epidemic of overdose and HIV infection that developed in the 1990s, opened North America’s first supervised injection facility, Insite, in 2003. Research has demonstrated multiple benefits of Insite, including a substantial local reduction in opioid overdose mortality (Marshall, Milloy, Wood, Montaner, & Kerr, 2011). Since opening in 2003, no deaths have ever occurred at Insite.

Increases in opioid prescribing drove rising opioid overdose death rates at the beginning of the 21st Century across the United States, resulting in the recognition of an opioid epidemic. Between 1999 and 2008, prescription opioid-related overdose deaths, sales of prescription opioids, and treatment admissions for prescription opioid use disorders, each increased by four-fold or more (Centers for Disease & Prevention, 2011). The rise in prescription opioid-related overdose deaths slowed in 2010, a year when the formulation of long-acting oxycodone was changed to make it harder to insufflate or inject (Cicero, Ellis, & Surratt, 2012), propoxyphene was taken off the market, and Florida restricted high volume opioid prescribing through pill mills (Dart et al., 2015, Kennedy-Hendricks et al., 2016; Larochelle, Zhang, Ross-Degnan, & Wharam, 2015; Rutkow et al., 2015). Prescription drug monitoring programs proliferated during this period as an effort to make opioid prescribing safer (Delcher, Wagenaar, Goldberger, Cook, & Maldonado-Molina, 2015; Green, Zaller, Rich, Bowman, & Friedmann, 2011; Paulozzi, Kilbourne, & Desai, 2011). In conjunction with these opioid stewardship initiatives, overdose education and naloxone rescue for people using prescription opioids was increasingly considered a necessary component of the response to the opioid epidemic. As a result, all but three U.S. states in 2016 have laws supporting naloxone provision to lay persons (Brodrick, Brodrick, & Adinoff, 2016). In recognizing opioid-related overdose as a major public health concern, the US Department of Health and Human Services highlighted naloxone rescue kit access and emergency overdose response as one of three priority areas to address this crisis in 2015 (“HHS takes strong steps to address opioid-drug related overdose, death and dependence," March 26, 2015). Though nation-wide systematic monitoring remains a challenge in Canada, similar increases in opioid prescribing and related harms were observed during the same time period (Fischer and Argento, 2012, Hospitalizations and Emergency Department Visits Due to Opioid Poisoning in Canada, 2016), with subsequent reductions in opioid prescribing following implementation of interventions, such as the adoption of prescription monitoring programs in the provinces of Ontario and British Columbia and delisting of long-activing formulations of oxycodone from public drug formularies in several provinces in 2012 (Murphy, Goldner, & Fischer, 2015).

Naloxone programming has demonstrated benefits in some localities in the context of escalating prescription opioid analgesic use and overdose. In San Francisco, for example, there was no increase in opioid overdose mortality during the period of expanding opioid access, notwithstanding data suggesting a large increase in the population of opioid injectors (San Francisco Sentinel Community Site (SCS) Drug Use Patterns and Trends, 2016). Nonetheless, a persistent number of opioid analgesic deaths – approximately 110 per year – led the local health department to offer naloxone prescriptions to patients on long-term opioids in selected primary care clinics. Some of the earliest efforts in naloxone co-prescription were made by Project Lazarus in Wilkes County, North Carolina, which saw a 70% decrease in prescription opioid-related overdose death rates during the implementation phase of the project from 2009 to 2010 (Albert et al., 2011). Naloxone co-prescribing was found to be acceptable to clinicians and it was associated with reductions in emergency department visits for opioid-related adverse events (Behar et al., 2016, Coffin et al., 2016).

These findings contributed to initiation of a national overdose education and naloxone distribution program through the Department of Veterans Affairs (Oliva et al., 2016) and informed the CDC chronic pain guidelines that encourage naloxone co-prescribing to patients on prescription opioids long-term for non-cancer pain (Dowell, Haegerich, & Chou, 2016).

As opioid prescribing rates declined and novel opioid formulations that deter injection were developed, the United States and western Canada witnessed a dramatic increase in heroin overdose rates in the 2010s, during which time rates more than tripled (Illicit Drug Overdose Deaths in BC January 1, 2007–October 31, 2016; Rudd, Seth, David, & Scholl, 2016). This brought attention back to illicit opioid users and the original target population of naloxone programming. Heroin use and heroin-related overdose have surged as people transition from prescription opioids (Mars, Bourgois, Karandinos, Montero, & Ciccarone, 2014; Rudd, Aleshire et al., 2016; Unick, Rosenblum, Mars, & Ciccarone, 2013). However, the emergence of synthetic opioids in the illicit opioid markets (both traditional heroin and illicit prescription opioids) during this era have contributed to ongoing high overdose rates and presented new challenges to naloxone-based interventions.

Fentanyl, as an additive or substitute for heroin, offers several advantages or opportunities for individuals involved in the illicit drug trade. Because of the potency, it requires less bulk and weight to transport and distribute than heroin. It can be reliably manufactured from abundant chemical precursors in large quantities, whereas heroin requires an opium crop that must be produced in the open air. While fentanyl is currently the most popular illicitly manufactured opioid, there are many viable analogues that can be produced to evade distribution crimes (Suzuki & El-Haddad, 2017). People who use opioids may prefer to use fentanyl as it is highly lipid-soluble, thus rapid-acting, and 40 times more potent at the opioid receptor than heroin, which results in fast onset euphoria and pain relief. Many PWID describe the experience as like heroin, but more intense (Amlani et al., 2015; Ciccarone, Ondocsin, & Mars, 2017; Macmadu, Carroll, Hadland, Green, & Marshall, 2017). Like heroin, fentanyl has a half-life of approximately 3–7 h (Trescot, Datta, Lee, & Hansen, 2008), however, the duration of action of fentanyl is briefer, only 30–60 min for an intravenous injection, compared to 4–5 h for heroin. Heroin is lipophilic and therefore is transmitted rapidly to the central nervous system, however, once there it is converted to morphine, which is less lipophilic and therefore retained. However, fentanyl is highly and persistently lipophilic so it enters and exits the central nervous system rapidly. Therefore, fentanyl is both faster and shorter acting, and must be re-dosed frequently (meaning more injections per day).

Overdose deaths due to the use of illicitly manufactured fentanyl by people who use heroin have occurred sporadically for decades (Henderson, 1991, Martin et al., 1991). The first national outbreak of fentanyl-tainted heroin occurred across six jurisdictions in the eastern United States from 2005 to 2007, and accounted for an excess 1,013 deaths (Centers for Disease & Prevention, 2008). This outbreak seemed to be aborted by closure of a facility manufacturing illicit fentanyl in Mexico in 2006 (Centers for Disease & Prevention, 2008). The sharpest increase in synthetic opioid-involved deaths occurred in 2014, with a near doubling of rates from the previous year (Rudd, Aleshire et al., 2016). Fentanyl-tainted heroin has primarily impacted areas where white powder heroin is prevalent, and includes the Northeast, Midwest and Southeast regions of the United States and Western Canada (CDC, 2016). In some Northeastern states, fentanyl accounts for more than half of all fatal overdoses (CDC, 2016). As of 2017, western United States and Eastern Canada have been relatively spared. In the case of the US western states, this may be because of the predominance of black tar heroin, which produces a high that is more distinct from fentanyl and is a thicker substance that may be more difficult to mix with fentanyl powder. Counterfeit pills (e.g. labeled as Oxycodone, Norco) produced with fentanyl and fentanyl analogues may have also contributed to the growing overdose epidemic (CDC, 2016). The emergence and proliferation of counterfeits create further confusion in the illicit marketplace, which contributes to inconsistency of source and greater safety concerns over drug products (Armenian et al., 2017, Green and Gilbert, 2016, Sutter et al., 2017).

Several communities with strong naloxone programming or supervised injection facilities have been deeply affected by fentanyl overdose mortality. Between 2005 and 2011, Massachusetts had an opioid-related overdose death rate that plateaued between 8.0 and 9.9 per 100,000 people. Since 2012, the rate has climbed substantially each year to an estimated 25.8 per 100,000 people in 2015 (Data Brief: Opioid-related Overdose Deaths among Massachusetts Residents, 2016). Among opioid-related overdose deaths examined in 2016, 74% had toxicology positive for fentanyl. The province of British Columbia, Canada, has seen a steady increase in illicit drug overdose deaths from 5.9 per 100,000 in 2012 to 19.3 per 100,000 in 2016, with illicitly manufactured fentanyl-detected deaths accounting largely for the increase, despite rapid expansion of supervised injection facilities in the city of Vancouver and province-wide scale-up of overdose education and naloxone distribution (OEND) (Illicit Drug Overdose Deaths in BC, January 1, 2007–December 31, 2016). Public health authorities are struggling to adapt previously effective strategies such as OEND and SIFs to a new landscape dominated by synthetic opioids, even in locales with long established and comprehensive programs. Naloxone provision alone will be insufficient to stop this epidemic.