ADDICTION CLASSICS doi:10.1111/add.

13516

Addiction classics: Heroin overdose

Shane Darke
National Drug and Alcohol Research Centre, University of New South Wales, Sydney, New South Wales, Australia

ABSTRACT

Background and aims This narrative review aims to provide a brief history of the development of the heroin overdose
field by discussing a selection of major ‘classics’ from the latter part of the 20th century. Methods Papers considered
landmarks were selected from 1972, 1977, 1983, 1984 and 1999. Results Findings of earlier works suggest much of
what later research was to demonstrate. These include arguing that overdoses occurred primarily among tolerant older
users, that most ‘overdose’ deaths involved low morphine concentrations, that most overdoses involve polypharmacy, that
drug purity has only a moderate influence on overdose rates and that instant death following heroin administration is rare.
Conclusions Landmark studies of heroin overdose from the 1970s, 1980s and 1990s laid the foundations for
subsequent overdose research, mainly by identifying the major demographic characteristics of overdose cases, risk factors,
survival times and behaviours at overdose events.

Keywords Circumstances, heroin, mechanisms, mortality, overdose, toxicology.

Correspondence to: Shane Darke, National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, 2052, Australia.
E-mail: s.darke@unsw.edu.au
Submitted 1 May 2016; initial review completed 12 May 2016; final version accepted 27 June 2016

INTRODUCTION In this narrative review, I have selected works that I

The 1990s saw research emerge addressing the causes
and circumstances of heroin overdose that has continued
to this day. This wave of research (to which I have made
some contribution) challenged and, indeed, disproved
many cherished beliefs concerning overdose. This body
of work demonstrated that overdoses occurred primarily
among tolerant older users, not the very young [1–5].
Many heroin ‘overdose’ deaths appear to involve quite
low morphine concentrations [2–4,6–10]. What we term
‘heroin’ overdoses involve predominantly polydrug toxi-
city [2–4,10–13]. Drug purity has only moderate influ-
ence, and is not an overwhelmingly important factor
[14,15]. Contrary to belief instant deaths are rare, and
most appear to be a prolonged process [3,16]. Despite
time to intervene, responses by witnesses of overdose are
poor, due to factors such as fear of police involvement,
witnesses being intoxicated themselves or not recognizing
signs of acute respiratory distress [3,4,16–20]. Finally,
most overdoses are not suicides, or parasuicides, the vast
majority appearing to be unintentional [2–4,16,21].
What is extraordinary is that much of this was first stated
in the 1970s, yet the myths surrounding overdose conti-
nued to flourish.
consider to be landmarks in the field of heroin overdose.
By the very nature of such an endeavour, these were
subjective choices of works that influenced my work in
this field strongly. They are illuminating pieces that
remain rewarding reading, and are seminal works with
which anyone with an interest in the field should be
familiar. These works retain their relevance, as it would
appear that every time there is a high-profile death from
heroin use, old powerful myths concerning ‘killer’ heroin
arise in the press. The works presented here are powerful
antidotes to these myths.
THE CLASSICS
1972
We commence in the early 1970s, with a remarkable work
by Edward M. Brecher [22]. In the chapter on the ‘mystery’
of heroin overdose, he makes the astounding proclamation
that: ‘1. The deaths cannot be due to overdose. 2. There
has never been any evidence that they are due to overdose.
3. There has long been a plethora of evidence that they are
not due to overdose’ ([22], p. 103). Based upon early work
on the toxicology, epidemiology and circumstances of
heroin deaths, Brecher argued that heroin ‘overdose’ was

© 2016 Society for the Study of Addiction Addiction

2 Shane Darke
a catch-all term, applied to all unexplained heroin-related
deaths. The picture was, he believed, far more complex. It
was experienced, highly opioid-tolerant users who were
dying, not inexperienced users who would be most exposed
to variations in purity and the amount consumed.
Moreover, there was no difference in the purity of bags of
heroin found with fatal overdose cases and street seizures,
and the number of deaths had increased while the size of
heroin deals had decreased. Finally, users commonly
injected in groups, from the same heroin supply, and
multiple overdoses were rare. He concluded that: ‘These
deaths are, if anything, associated with “underdose” rather
than overdose’ ([22], p. 107].
What, then, did he believe was causing these deaths?
Most deaths were, in fact, polydrug toxicity deaths. To my
knowledge, this was the first time this was asserted. History
would prove him right [2–4,10–13]. The main drugs he
identified were other central nervous system (CNS)
depressants, notably alcohol and the barbiturates. Their
combined effects of respiratory depression resulted in
death. Essentially, the ordinary heroin dose that is safe
when sober may kill when drunk. The same applied to
barbiturates. In more recent years, as benzodiazepines
replaced barbiturates, the same association with opioid
overdose was seen [2–4,9,11,16].
Finally, rather than overdoses being sudden, Brecher
argued that in most cases heroin overdose was a prolonged
process, with ample time for intervention. The person did
not typically drop down dead, but went through an
extended process of respiratory depression, ending in
death. This is a remarkable, and clinically important,
insight. Again, later studies were to prove him right [3,16].
In one chapter, Brecher laid the foundations for all
subsequent overdose research: overdose was typically a
prolonged process allowing time to intervene; most
overdoses involve polydrug use; and it was experienced
users who should be considered in prevention and inter-
vention research.
1977
We move now to the late 1970s, with a seminal work from
forensic medicine by Monforte that greatly advanced our
understanding of overdose [23]. In this innovative work,
the toxicology of heroin-related deaths were compared
with those of heroin using homicide victims, thus addres-
sing directly the issue raised by Brecher as to whether these
were ‘true’ pharmacological overdoses. He found that in
three-quarters of overdose cases morphine (the major
metabolite of heroin) concentrations were no higher than
those of heroin using trauma victims. He argued that, in
most cases, death was not due to a toxic dose of morphine,
and that it was: ‘Misleading to apply the word “overdose” to
these deaths based solely on the blood morphine
© 2016 Society for the Study of Addiction
concentration’ ([23], p. 719). As with Brecher, the charac-
teristics and circumstances of death made it unlikely that
death was due to non-tolerant users. He also noted that
the typical route of administration among overdose cases
was by injection, a finding seen repeatedly in later years
[2–4].
So what did Monforte think was occurring? Again,
polypharmacy was brought to the fore. Three-quarters of
overdose cases involved multiple drugs, most prominently
alcohol and benzodiazepines. Specifically, there was a
negative correlation between alcohol and morphine
concentrations, suggesting that a lower heroin dose may
kill you when you are drunk. As Monforte noted, there
was: ‘a good possibility is that these persons died from the
combined central nervous system (CNS) effects of ethanol
and morphine’ ([23], p. 722). Diazepam, a quick-onset,
long-acting benzodiazepine, was noted specifically. As
noted above, diazepam would be reported frequently in
subsequent work in this field.
Finally, it was again reported that instant death in
‘overdose’ was rare, with most deaths being delayed. The
common misconception of sudden death was challenged
again. There is time to intervene.
1983
We move to a brace of papers examining overdose deaths
among US servicemen by Manning and colleagues
[24,25]. These papers were the first to use psychological
autopsies to examine the circumstances of, and responses
to, overdose. This represented a major advance in our
understanding of what occurs at the scene of an overdose.
The emerging picture of death being predominantly
among experienced users, rather than neophytes, was sup-
ported. The typical case was someone: ‘with considerable
heroin experience and expertise’ ([24], p. 164) who had
injected the drug. The authors argued that these deaths
were not, as assumed commonly, due to ignorance, incom-
petence or indifference. They also noted that overdose
deaths were rarely suicide. This is an important clinical
finding, as the high rates of depression among opioid users
lead many to assume that overdose are para-, or de-facto,
suicides. They are not, and their correlates (and thus what
may prevent them) differ [2–4,16,21].
The emerging picture of polydrug use was again noted.
Specifically, alcohol was associated strongly with these
deaths. The typical pattern was to have a ‘nightcap’ of
heroin following a heavy drinking session. Again, we see
a pattern of experienced users dying from polypharmacy,
not from ‘killer heroin’ of remarkable potency.
The psychological autopsies confirmed the earlier
works discussed here, suggesting that instant death was
the exception, not the rule. The more common pattern
was to go to bed after using heroin and alcohol, and die
Addiction

after a prolonged period of respiratory depression and/or
aspiration of vomitus. For the first time in the literature
there was comment on the behaviour of witnesses.
Witnesses were reluctant to seek help. Anything else was
tried rather than seek medical help, including cold showers
and the injection of saline. Help was sometimes only
sought some 3 hours into the overdose. This reluctance
to seek help would be found time and again in later years
[3,4,16–20].
In these studies, for the first time, we have a picture of
the overdose event, and the behaviour of witnesses to it.
1984
In the following year, Ruttenber & Luke [26] published a
toxicological study that progressed our understanding of
the role of alcohol in heroin overdose significantly. The
authors examined the toxicology of an ‘epidemic’ of heroin
overdose deaths in the District of Columbia in the United
States. Like Monforte in the 1970s [23], the authors
compared the toxicology of heroin overdose deaths with
opiate users who died from disease or trauma. Heroin
overdose cases were more likely to have alcohol present
and to have heavier blood alcohol concentrations.
Moreover, alcohol was more likely to be present, and in
higher concentrations, in the epidemic phase than in other
periods. In a statement that echoes our earlier classics, the
authors stated: ‘Our data provide statistically significant
evidence that the combination of ethanol and heroin
substantially influences mortality’ ([26], p. 17). It is worthy
of note that in follow-up work, published in 1991,
Ruttenber et al. [27] demonstrated a significant negative
correlation between morphine and alcohol concentrations
among overdose fatalities.
It is again worthy of note that almost all cases involved
injected heroin, and the age of overdose cases was in the
early 30s. The authors found an association between
heroin purity and the incidence of deaths. Purity is not
irrelevant, but it is not the sole factor, as it would be if true
overdose were the predominant scenario. Alcohol was also
an independent risk factor for ‘heroin’ overdose.
1999
Our final classic is a theoretical paper by White & Irvine
from the field of pharmacology, which strove to provide
mechanisms to explain the demographic and clinical
characteristics of overdose [28]. In particular, the authors
were interested in why it was older, experienced users
who made up the bulk of deaths. To my knowledge, this
is the first attempt to provide a theoretical underpinning
for opioid overdose.
Why, then, is it the older, experienced user who appears
most at risk? White & Irvine argued that the development
© 2016 Society for the Study of Addiction
Opioid overdose 3
of opioid tolerance is not a unitary phenomenon.
Specifically, they suggested that tolerance to the respiratory
depression associated with heroin administration is less
than complete. Crucially, it may also be slower to develop
than tolerance to the euphoric effects of the drug.
Effectively, this means that users will require more of the
drug to achieve the hedonistic effects, while their respira-
tory tolerance does not keep up. The risk of severe respira-
tory depression, and possible death, thus increases. One
consequence of this may be a higher risk of overdose
among experienced opioid users. Again, contrary to
popular belief, it is not the inexperienced user who would
be at most at risk, but the ‘old hand’ who is tolerant to
the hedonistic effects. Consistent with this hypothesis,
severe respiratory depression following heroin injection
has been demonstrated among highly tolerant heroin
maintenance patients [29].
Why, then, is polypharmacy the predominant clinical
presentation? White & Irvine argue that the concomitant
use of benzodiazepines or alcohol is not simply an artefact
of polydrug use patterns, but actively increases the risk of
death from heroin administration. While both alcohol
and the benzodiazepines are relatively weak respiratory
depressants, in the presence of a potent depressant such
as heroin they augment its respiratory effects. Both alcohol
and the benzodiazepines act upon the γ-aminobutyric acid
(GABA) receptor system, a major factor in respiratory
control system. The effect of all three drugs upon the GABA
system acts to inhibit respiration, and their combination
effect increases the likelihood of death.
For the first time, we had a testable model of overdose.
CONCLUSIONS
The field of opioid overdose has remained active, and
advances continue to be made in both understanding and
preventing overdose. Work has continued during this
century on identifying environmental risks such as the
period immediately following prison release or detoxifica-
tion, the protective effects of drug treatment programmes
and on the provision of the opioid antagonist naloxone
directly to heroin users [30–35]. We should always be
aware that the last few decades of the 20th century laid
the foundations for this work. This pioneering work identi-
fied the major demographic characteristics of overdose
cases, risk factors, survival times and behaviours at over-
dose events. I recommend these classics to the reader.
Acknowledgements
The National Drug and Alcohol Research Centre at the
University of NSW is supported by funding from the Aus-
tralian Government.
Addiction
4 Shane Darke
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