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International Journal of Drug Policy
journal homepage: www.elsevier.com/locate/drugpo
Commentary
The triple wave epidemic: Supply and demand drivers of the US opioid
overdose crisis
Daniel Ciccarone
Department of Family and Community Medicine, University of California San Francisco, United States
ARTICLE INFO
Keywords:
Fentanyl
Heroin
Opioid
Overdose
Injection drug use
Introduction
The US mortality rate has gone up three years in a row from 2014 to
2017 (Xu, Murphy, Kochanek, & Arias, 2016;Murphy, Xu, Kochanek, &
Arias, 2018;Kochanek, Murphy, Xu, & Arias, 2017). Correspondingly,
life expectancy at birth has declined; the first triple year decline since
World War One and the devastating influenza pandemic one hundred
years ago (Tejada Vera, Bastian, & Arias, 2017). Most of the top ten
causes of death are declining year over year; however, the third leading
cause of death, unintentional injuries, has climbed in rate and rank
since 2014 (Xu et al., 2016). Driving this are deaths due to drug poi-
soning which exceeded 70,000 in 2017 (Hedegaard, Miniño, & Warner,
2018). Annual deaths due to drug overdoses now exceed those from
motor vehicle deaths, gun violence and even HIV at the height of the
1990s HIV epidemic (Katz, 2017).
The triple wave epidemic: opioid pills, heroin and synthetic
opioids
The US is suffering a triple wave epidemic of overdose deaths from
three classes of opioids: prescription opioid pills (“semi-synthetic
opioids”in Fig. 1), heroin and synthetic opioids other than methadone
(Ciccarone, 2017). Fig. 1 shows three waves of opioid mortality, each
wave cresting on top of the one before it. In the first wave, overdoses
related to opioid pills, started rising in the year 2000 and have steadily
grown through 2016. The second wave saw overdose deaths due to
heroin, which started increasing clearly in 2007, surpassing the number
of deaths due to opioid pills in 2015. The third wave mortality has
arisen from fentanyl, fentanyl analogues and other synthetic opioids of
illicit supply, climbing slowly at first, but dramatically after 2013. Data
from 2017 show synthetic opioid deaths continuing to rise, reaching a
peak of over 28,000, while opioid pill and heroin overdose deaths
leveled off, albeit at very high levels of approximately 15,000 deaths in
each category (Hedegaard et al., 2018).
Supply and demand drivers
To address this crisis, its supply and demand drivers need to be
better understood; both forces are needed to create the immense waves
of consumption and their consequences that are occurring. Historians
have observed the implications of supply in several opioid misuse cycles
beginning with morphine in the latter half of the 19
th
century
(Courtwright, 2001b;Musto, 1999). Isolated in 1805 by the German
pharmacist Friedrich Serturner, morphine was mostly dispensed by
physicians in America, particularly to women (Courtwright, 2001a).
Thus the subsequent misuse problem was iatrogenic, exacerbated by the
technological advance of the hypodermic syringe (Courtwright, 2001b,
2001b).
Heroin (diacetylmorphine) had a short life as a licit medication.
There have been a number of illicit heroin waves beginning around the
1920s, the first of which may have been due to restriction on licit
supplies driving its use underground. Consumption of all kinds occurs
within an economic and cultural framework and both demand-side and
supply-side forces can bring innovation to established consumption
patterns. The upswings in American heroin use in the 1940s and’70 s
were in part stimulated by strong social and cultural elements, where
heroin use often conferred an outsider status, signaling the rejection of
mainstream values (Courtwright, 2001b). They also had strong supply-
side forces with the post-WW2 emergence of the Italian and French
‘connection’supplying heroin to the US (Courtwright, 2001b) and new
sources of heroin imported from Southeast and Southwest Asia in the
1970s (McCoy, 2003). In the 1990s, a new form of heroin, produced by
Colombian transnational criminal organizations (TCOs), was brought
into the United States resulting in increased heroin use and adverse
https://doi.org/10.1016/j.drugpo.2019.01.010
International Journal of Drug Policy xxx (xxxx) xxx–xxx
0955-3959/ © 2019 Elsevier B.V. All rights reserved.
Please cite this article as: Ciccarone, D., International Journal of Drug Policy, https://doi.org/10.1016/j.drugpo.2019.01.010
consequences (Ciccarone, 2009;Ciccarone, Unick, & Kraus, 2009).
In sum, since the uptake of morphine and subsequent licit and illicit
opioids, the US has experienced multiple waves of opioid misuse and
their medical consequences caused by the forces of supply (iatrogenic
and new illicit sources) and demand (social, cultural and new tech-
nologies for use). In the current triple wave epidemic, we see both
forces at work again. On the supply side, we have witnessed the ia-
trogenic sourcing of opioid pills, a new source-form of refined heroin
and an illicit opioid sub-class, fentanyls, resurfacing from a new source.
On the demand side, there are social and structural root causes of
opioid use that have led to population dependency on opioids; starting
with pills, yet leading to spill-over effects driving heroin and subse-
quently fentanyl demand.
Wave one: prescription opioid pills
The supply side drivers underlying the first wave of prescription
opioid overdose have been extensively discussed (Madras, 2017;Van
Zee, 2009). Wave one is often considered to have been driven ia-
trogenically with a tripling of opioid prescriptions starting in the 1990s
and peaking around 2011 (Kolodny et al., 2015). This increase in pre-
scriptions has been correlated to rising adverse consequences, particu-
larly opioid overdose (Centers for Disease Control & Prevention, 2011).
The introduction of extended release long-acting (ERLA) opioid for-
mulations support both supply-side and demand-side pressures. ERLAs
are a source of opioid in a novel form with a technological advance that
allowed higher, longer lasting doses in a single capsule. However, the
ease with which their delayed release mechanisms could by bypassed
and the whole dose discharged at once, for instance by crushing and
insufflating (nasal snorting) or injecting, led to a wave of misuse
(Cicero, Ellis, & Surratt, 2012;Mars, Bourgois, Karandinos, Montero, &
Ciccarone, 2014).
A demand-side argument has been introduced examining the
structural factors that might be driving the epidemic. The most com-
pelling structural determinants include an aging population with rises
in reported pain and disability, economic distress, declining social co-
hesion and rising psychological malaise that may have led an at-risk
population to seek opioids in the first place (Dasgupta, Beletsky, &
Ciccarone, 2018).
Wave two: heroin
Coincident with rising heroin-related deaths, the number of heroin
users, especially young heroin users, has been increasing since the mid-
2000s (Center for Behavioral Health Statistics and Quality, 2017;
Kilmer et al., 2014). The first two overdose waves, from opioid pills and
heroin, have been termed ‘intertwined epidemics’(Unick, Rosenblum,
Mars, & Ciccarone, 2013). Young and new heroin users have described
transitioning to heroin from opioid pills as their growing dependence
required larger and more consistent pill supplies than they could obtain
either by prescription or on the street. The more ready availability of
high purity, low cost heroin made the switch to heroin economically
logical and difficult to resist (Mars et al., 2014).
Drug treatment data show that in successive cohorts from the 1960s
through the 2000s, patients admitted to treatment with heroin use
disorder increasingly reported starting their opioid dependency with
opioid pills (Cicero, Ellis, Surratt, & Kurtz, 2014). However, this has
begun to change as an increasing proportion of heroin use disorder
patients entering treatment report heroin as their first experience of an
opioid (Cicero, Kasper, & Ellis, 2018). Overdoses due to heroin began to
accelerate in 2011. In late 2010 OxyContin, a brand name ERLA for-
mulation of oxycodone, was reformulated to be abuse-deterrent. The
reformulation of this popular diverted opioid pill may have had the
unintended consequence of driving a small proportion of the at-risk
population to heroin (Cicero et al., 2012).
Although overlapping and related, the first and second opioid
overdose waves show some contrasts in age and regional distribution
that require explanation. Examining the years 2012–2014, the age
distribution of patients hospitalized for opioid pill overdose had its
largest peaks in the 50 to 64 year old group. Meanwhile, the peak age
group for heroin overdose admissions was 20 to 34 year-olds. In this
data we see possible evidence of population level transitions from
opioid pills to heroin use as the rates for overdose among 20–34 year-
olds declined for opioid pills while, in the same time period, increased
for heroin (Unick & Ciccarone, 2017). In sum, we have seen elements of
demand-side drive in wave two, with rising numbers of heroin users
transitioning from opioid pill dependency followed more recently by
younger persons initiating first with heroin.
Geographic disparities are also evident: opioid pill overdose is
Fig. 1. Opioid Overdose Deaths by Type of Opioid.
D. Ciccarone International Journal of Drug Policy xxx (xxxx) xxx–xxx
2
relatively even across the country whereas heroin overdose is much
higher in the US Northeast and Midwest regions, along with higher
rates of increase (Unick & Ciccarone, 2017). Some of this regional
disparity may be endemic, stemming from the 1970s, but there are also
significant new supply-side forces shaping it. A dramatic transformation
in the US heroin supply, including changes in its country of origin, has
occurred in the last 10 years. Prior to 2000, heroin was imported from
four source regions/countries in the world, including Southeast Asia,
Southwest Asia, Mexico, and South America (Colombia). The 2000s
began an era in which most US heroin was transshipped by TCOs from
two countries: Colombia and Mexico (US Drug Enforcement
Administration, 2015). Regional heroin distribution became starkly
divided with Colombian-sourced heroin predominant in the eastern US
while ‘black tar’heroin from Mexico the major source-form in the
western US (Ciccarone, 2009;Ciccarone et al., 2009). Accelerating this
trend from oligopoly to monopoly, Mexican TCOs have increasingly
dominated the US heroin market with their market share increasing
from 50% in 2005 to 90% in 2016 (US Drug Enforcement
Administration, 2017b).
Mexican-sourced heroin is also becoming more refined. From 2005
to 2012, a growing and substantial proportion of analyzed heroin
samples obtained in eastern US cities by the US Drug Enforcement
Administration (DEA) for its Heroin Domestic Monitor Program were
from an unknown source and of unknown quality (Drug Enforcement
Administration, 2016). Subsequent DEA analyses have led to the con-
clusion that a more refined heroin has emerged from Mexican sources.
This so-called ‘Mexican White’is a mimic of Colombian-sourced powder
heroin, replacing it in its traditional retail outlets of the Northeast and
Midwest (US Drug Enforcement Administration, 2015).
Wave three: synthetic opioids
Synthetic opioids in the heroin supply, chiefly illicitly produced
fentanyl, are responsible for the third wave of overdose mortality
(Ciccarone, 2017;NIDA, 2018). ‘Heroin’, particularly in the Northeast
and Midwest, the regions with the greatest increases in wave two
overdose, currently exists as fentanyl-adulterated and/or fentanyl-sub-
stituted heroin (FASH) (Ciccarone, Ondocsin, & Mars, 2017). Illicitly
manufactured fentanyl is integrated into the illicit drug supply and sold
as ‘heroin’in powder form, or as counterfeit opioid or benzodiazepine
pills (Gladden, Martinez, & Seth, 2016).
Fentanyl is the main chemical in a growing family of chemical
analogues. These analogues come in a range of morphine-equivalent
potencies with some such as butyryl-fentanyl being less potent than
fentanyl by weight while others have much greater potency (Suzuki &
El-Haddad, 2017). In addition, there are other novel synthetic opioids
in circulation including U47700 and U48800. The greatest concern
arises from a branch of the fentanyl family that includes some ex-
ceedingly potent opioids including carfentanil, sufentanil and re-
mifentanil. It is unclear whether these extremely potent fentanyls will
become established elements in the opioid marketplace or if they are
just accidents or experiments in the rapidly evolving illicit opioid
supply.
According to the US Drug Enforcement Administration (DEA), the
main source of illicitly manufactured fentanyls is China. Fentanyls
sourced from China take a number of routes on their way into the US
including internet purchases, routing through Canada (typically pill
form), or through Mexico in powder or pill forms (US Drug Enforcement
Administration, 2016). Perhaps the most revealing aspect of the supply
that fuels the US fentanyl epidemic is its regional discreetness. Com-
paring drug seizure data with overdose death data one finds remarkable
geographical correlation between fentanyl seizures and synthetic opioid
overdoses (Gladden et al., 2016). These fentanyl events overlap in the
same regions as wave two heroin overdose: the Northeast and Midwest.
The reasons for this regional disparity are unclear. One possibility is
that fentanyl distribution is regionally orchestrated by a branch of the
Sinaloa TCO (US Drug Enforcement Administration, 2017b). Another
hypothesis is that source-forms of powder heroin, predominant in the
Northeast and Midwest, are more easily adulterated with powder fen-
tanyl than solid ‘black tar’heroin, which predominates in the western
US (Carroll, Marshall, Rich, & Green, 2017;Ciccarone, 2017). Such
stark regional disparities support the notion that the third wave is a
supply-side event (Mars, Rosenblum, & Ciccarone, 2018). A demand or
culturally driven event, such as through entrepreneurial or individual
internet purchases, would more likely have led to a more even geo-
graphic spread of fentanyl-related overdose or one that reflected similar
social conditions in separate geographical locations.
Ethnographic research with persons who use heroin confirm that the
introduction of FASH has been unexpected and unsettling, that fentanyl
was not a demand-driven phenomenon and that there is a range of
desirability for FASH from abhorrence and avoidance through accep-
tance to enthusiasm (Carroll et al., 2017;Ciccarone et al., 2017;Mars,
Ondocsin, & Ciccarone, 2018). Those who favor fentanyl are never-
theless hampered from choosing it in the market place by its concealed
identity as ‘heroin’or counterfeit brand name pills (Ciccarone et al.,
2017;Mars, Ondocsin et al., 2018;Mars, Rosenblum et al., 2018). Im-
portantly, cultural idioms for fentanyl have been slow to emerge despite
four years of steady supply; slang terms have arisen for most desired
illicit drugs and their absence is evidence for a lack of strong demand.
Consequentially, emergence of slang can be seen as a marker for
growing acceptance of fentanyl.
In addition to the dangerous potency of fentanyl, ethnographic
observations support the notion of a possibly greater danger: rapid
changes in potency and purity, as well as varying mixtures of heroin,
fentanyl and its analogues (Ciccarone, 2017;Ciccarone et al., 2017;
Mars, Ondocsin et al., 2018;Mars, Rosenblum et al., 2018). Australian
research on heroin overdose has shown that fluctuations within a wider
range of street heroin purity, particularly when around a higher mean
purity level, are an independent predictor of fatal overdose (Darke,
Hall, Weatherburn, & Lind, 1999). Vicissitudes in potency/purity/
mixture in the fentanyl street market may be discovered to have pro-
found effects on the overdose rate in a given location.
In summary, all three waves have impressive supply-side drivers
including excessive prescribing of medication, a new form of highly
refined Mexican-sourced heroin and a new illicit source of synthetic
opioids adulterating heroin and counterfeit pills. Demand for opioid
pills partially drove demand for heroin while demand for heroin un-
suspectingly feeds demand for synthetics-as-substitute. What is driving
increases in opioid mortality now are deaths due to FASH. The second
and third waves are regional, with the Northeast (including Mid-
Atlantic) and Midwest (including Appalachia), the most affected re-
gions.
There are other medical consequences, in addition to overdose, that
are growing in concern. The change from opioid pill misuse to heroin
involved, for many, a change in route of administration from oral in-
gestion to intravenous injection. While heroin can be smoked or in-
sufflated, it tends, in the US, to be injected (Ciccarone, 2019). This
raises concerns about the transmission of blood-borne viruses such as
hepatitis C and HIV. The US has recently had two documented injec-
tion-drug-related HIV outbreaks in Scott County, Indiana and eastern
Massachusetts (Peters et al., 2016;US Centers for Disease Control &
Prevention, 2018).
Addressing the fentanyl crisis
The triple-wave opioid overdose epidemic is an intertwined, three
drug sub-class epidemic. To comprehend and address it fully the drivers
of each wave need to be elucidated. Positive supply shocks have his-
torically led to drug epidemics and the same can be seen in the current
opioid crisis. Fentanyl, in particular, comes as a positive supply shock
leading to disastrous consequences. It is thus tempting to focus efforts
on controlling supply. There is evidence that supply-side interventions
D. Ciccarone International Journal of Drug Policy xxx (xxxx) xxx–xxx
3
can work if part of a comprehensive program that also includes demand
reduction (Caulkins, Reuter, Iguchi, & Chiesa, 2005). Unipolar supply-
side interventions however, may cause paradoxical unwanted results;
for example see (Ciccarone et al., 2009). These phenomena may be
occurring within the current crisis. Downward pressure on opioid pre-
scribing may be driving a portion of the at-risk population from opioid
pill misuse to heroin, thus exposing them to the even more dangerous
family of fentanyls. Another driver of unintended consequences may
have been the reformulation of ERLA opioids to abuse-deterrent for-
mulations, examples of which include OxyContin and Opana, with
misuse of the latter implicated in the Scott County Indiana HIV out-
break (Broz et al., 2018). The goals of curtailing excessive prescribing
practices or creating abuse-deterrent formulations may be reasonable,
but the untoward consequences must be recognized, monitored and
responded to accordingly.
The end of interdiction?
Regarding fentanyl, supply-side interventions include source control
and interdiction in the drug supply chain. Considering source control, it
is crucial to find areas of cooperation between the United States and the
Government of China to improve monitoring, regulation and enforce-
ment of pharmaceutical and chemical manufacturing in order to deter
illicit suppliers (Pardo, 2018). Bilateral efforts by governmental agen-
cies in both countries have led to an expanding list of controlled psy-
choactive substances, including opioids and precursors, leading to dis-
cussions regarding scheduling fentanyl as a class (Knierim, 2018).
Interdiction will be challenging given the size of illicit fentanyl flows. In
2016, a mere 668 kg of fentanyl was seized in the US (Baum, 2017), a
fraction of the estimated 11 metric tons of cocaine seized in 2016 at the
US Southwest Border alone (US Drug Enforcement Administration,
2017a). Fentanyl’s high potency allows shipment in small volumes.
Considering a seizure to importation ratio of 1:4, a total of 2.6 metric
tons of fentanyl may have been distributed in the US in 2016. This
would fit into approximately 10 industrial drum barrels –a tiny volume
that if divided up over the huge trade that occurs across the Pacific Rim
constitutes a proverbial needle in a haystack.
The “Iron Law of Prohibition”suggests that highly potent-by-vo-
lume drugs like fentanyl are expected due to the honing effects of in-
terdiction (Beletsky & Davis, 2017). Following this is the concern that
constraining the mother chemical fentanyl too robustly and too rapidly
will foster the supply of fentanyl analogues. The number of known
fentanyl analogues exceeds 60; the number of potential fentanyl ana-
logues could exceed 600. Care must be taken not to foster the ingenuity
and creativity of the illicit drug manufacturers to push in even more
dangerous directions. Based on this concern, the DEA has imposed a
first-ever class restriction on the family of fentanyls, the utility of which
is uncertain.
Surveillance of the drug supply
One supply-side intervention with potentially positive impact is
drug surveillance. Investments in drug monitoring, identification and
data collection could assist in interdicting supply (Pacula & Powell,
2018). US government officials have called for greater public safety and
public health collaboration to address this crisis. One way for these two
domains to work together is by increasing local drug surveillance –with
sharing of the data. Local criminal justice systems have a ready pool of
geo-located analyzable drug samples in their crime labs. Analysis of
drug samples and dissemination of the findings could be achieved in
rapid cycles and enhance our understanding of the drugs in circulation
and especially how rapidly heroin, FASH and fentanyl analogue mix-
tures are changing.
Improved surveillance would benefit not only the interdiction and
public safety side but also the public health side including first re-
sponders, emergency and hospital clinicians as well as those who work
in community based programs serving the affected population
(Ciccarone, 2017). Point of use testing or drug checking is an intimate
form of surveillance that is emergent in the US because of the FASH
crisis. Evidence for its utilization is growing (Peiper et al., 2018), al-
though concerns have also been raised (McGowan, Harris, Platt, Hope,
& Rhodes, 2018).
Harm reduction
Considering the inadequate and paradoxical effects of current
opioid supply interventions, supply-side policies must be combined
with sufficient investments in and expansion of effective prevention,
substance use treatment and harm reduction (Pacula & Powell, 2018).
Opioid use disorder has a number of medical treatment options that
have been shown to be medically efficacious as well as cost-effective
(Volkow, Frieden, Hyde, & Cha, 2014). The US Surgeon General has
called for greater distribution of naloxone, the opioid antagonist used to
treat an opioid pill, heroin or fentanyl overdose (US Surgeon General,
2018). Getting wider distribution of naloxone into the community is an
essential strategy in the current epidemic (Fairbairn, Coffin, & Walley,
2017;Wheeler, Jones, Gilbert, & Davidson, 2015). Sterile syringe pro-
vision must be greatly expanded to meet the increasing population at
risk. Drug surveillance, discussed above, can be utilized as a harm re-
duction strategy. Supervised consumption spaces can aid in prevention
of overdose and reduce HIV and HCV transmission risks (Dolan et al.,
2000;Marshall, Milloy, Wood, Montaner, & Kerr, 2011;Potier,
Laprévote, Dubois-Arber, Cottencin, & Rolland, 2014). These services
can act as a safety net or hub for persons at risk and provide them with
necessary resources and referrals to services (Kerr, Small, Moore, &
Wood, 2007).
Conclusion
A crisis level response is needed to address the triple wave epidemic.
In the 1990s, US government intervention, albeit slow to start, was
essential in curtailing the HIV epidemic. The Ryan White Care Act led to
a dramatic increase in funding for HIV prevention and treatment. That
coupled with medical progress led to a dramatic decrease in HIV in-
cidence, morbidity and mortality. The economic and social costs of the
opioid crisis are enormous, with estimates approaching $80 billion per
year. Estimates to address it range from $60 billion for treatment over
the next 5 years (Simmons, 2017) to $100 billion for a multi-pronged
approach to prevention, treatment and community resilience efforts
(Katz, 2018). The opioid epidemic is the latest phase of a multi-decade
increase in drug-related mortality (Jalal et al., 2018). With overdose
deaths increasing steadily since 1979, regardless of the primacy of any
particular drug, more resolve is needed to address the structural de-
terminants of this relentless epidemic.
Conflicts of interest
Dr Ciccarone reports receiving consulting fees from Mallinckrodt
Pharmaceuticals and Nektar Therapeutics.
Acknowledgements
I gratefully acknowledge research funding from US National
Institutes of Health, National Institute of Drug Abuse Grant DA037820.
I thank Dr. Sarah Mars for extensive feedback and editing and Dr. Jay
Unick for creating Fig. 1.
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