Mortality related to pharmacotherapies for opioid dependence: a comparative analysis of coronial records
Drug and Alcohol Review (July 2007), 26, 405 – 410
Mortality related to pharmacotherapies for opioid dependence: acomparative analysis of coronial records
National Drug and Alcohol Research Centre, University of New South Wales, Australia
AbstractIntroduction and Aims. The aim of this study was to compare the mortality associated with oral naltrexone, methadoneand buprenorphine in opioid dependence treatment, employing a retrospective data analysis using coronial and prescriptiondata. Design and Methods. The number of deaths were identified through national coronial data and number of treatmentrecipients were estimated from 2000 to 2003 prescriptions and restricted medications data. Mortality rates were expressed asdeaths per number of treatment episodes and per person-years at high and low risk of fatal opioid overdose. Results. Thirty-twooral naltrexone, one buprenorphine and 282 methadone-related deaths were identified. Mortality rates in the highest risk periodin deaths per 100 person-years were 22.1 (14.6 – 32.2) for oral naltrexone following treatment cessation and 3.0 (2.3 – 3.9) formethadone during treatment induction. Rates in the lowest risk period in deaths per 100 person-years were 1.0 (0.3 – 2.2)during oral naltrexone treatment and 0.34 (0.3 – 0.4) during post-induction methadone treatment. The relative risk of death fororal naltrexone subjects was 7.4 times (high-risk period, p 5 0.0001) or 2.8 times (low-risk period, p ¼ 0.055) that ofmethadone subjects. Discussion and Conclusions. This is the first comparison of mortality associated with these threepharmacotherapies for opioid dependence. The risk of death related to oral naltrexone appears higher than that related tomethadone treatment. [Gibson AE, Degenhardt LJ. Mortality related to pharmacotherapies for opioid dependence: acomparative analysis of coronial records. Drug Alcohol Rev 2007;26:405 – 410]
Key words: buprenorphine, methadone, mortality, naltrexone, opioid dependence.
the primary drug for opioid maintenance pharmaco-
therapy  and plays an important role in retaining
Opioid dependence is a chronic, relapsing disorder
patients in treatment, improving health, reducing cri-
[1,2] associated with elevated mortality risk, with death
minal activity and decreasing heroin and other drug use
most commonly from opioid overdose [2 – 5]. The
. Buprenorphine is a more recently developed medi-
mortality rate among untreated opioid-dependent in-
cation that is being prescribed increasingly in many
dividuals has been estimated at 0.9 per 100 person-
countries [8,9] and is similarly effective to methadone in
years . Reducing this mortality risk is an important
terms of retention and suppression of heroin use .
aim of opioid dependence treatment. However, users
Naltrexone, in contrast, has been available for many
often cease treatment; and that mortality risk will differ
years but has remained little-used due to low interest
during and following the treatment episode depending
among opioid-dependent individuals and poor compli-
upon the nature of the treatment modality. The current
ance with treatment [5,11,12]. No significant benefit of
study compares mortality risk related to three pharma-
naltrexone over placebo has been found in terms of
cotherapies for opioid dependence: naltrexone, bupre-
retention, side effects or relapse to heroin use .
Each of these treatments bears some mortality risk,
The range of maintenance pharmacotherapy treat-
which differs over the course of treatment due to the
ments available for opioid dependence include opioid
different mechanisms of drug action. Methadone
antagonists such as naltrexone, partial opioid agonists
provides some cross-tolerance to opioids, so once
such as buprenorphine and full opioid agonists such as
inducted into treatment recipients have a lower over-
methadone. For several decades, methadone has been
dose mortality rate than untreated opioid-dependent
Amy E. Gibson MPH BSc (Hons) BA, Senior Research Officer, National Drug and Alcohol Research Centre, University of New South Wales,Australia, Louisa J. Degenhardt PhD, MPsychol (Clinical), BA (Hons), Senior Lecturer, National Drug and Alcohol Research Centre, Universityof New South Wales, Australia. Correspondence to Amy Gibson, NDARC, UNSW, Sydney, NSW, Australia 2052.
Received 17 July 2006; accepted for publication 18 December 2006.
ISSN 0959-5236 print/ISSN 1465-3362 online/07/040405–06 ª Australasian Professional Society on Alcohol and other DrugsDOI: 10.1080/09595230701373834
subjects [14,15]. During induction, however, the risk of
as used in routine clinical practice. This report uses
fatal opioid overdose is high, with one study estimating
coronial data to quantify and directly compare the
7.4 deaths per 100 patient-years in the first 2 weeks of
mortality associated of oral naltrexone with that of
methadone treatment, compared to 0.07 deaths per 100
buprenorphine and methadone treatment for opioid
patient years beyond 2 weeks , and another study
dependence in Australia, including deaths both during
finding that 21% of deaths in methadone treatment
and after an episode of treatment. This will provide the
occurred during the first week . Death is caused
first estimate of the mortality rate related to oral
primarily by respiratory failure or complications arising
from opioid overdose, and methadone is usually
detected in post-mortem toxicology [18,19].
Buprenorphine has a longer mechanism of action
estimate the number of people receiving phar-
than methadone, with a flatter dose – response curve,
macotherapy for the treatment of opioid depen-
so that high doses prolong but do not increase the peak
effects , making subjects less likely to experience a
estimate the number of deaths related to these
fatal overdose . The great majority of all fatal over-
doses have involved the concomitant administration
estimate mortality rates according the number
of other respiratory-depressant drugs, usually ben-
of treatment episodes, and among periods of
buprenorphine-only deaths have been reported .
Opioid overdose deaths in France have decreased sub-
stantially since the introduction of buprenorphine and the mortality rate attributed to buprenorphine treat-
The number of deaths related to naltrexone, buprenor-
ment has been estimated at 0.24 per 1000 patients .
phine and methadone were determined by keyword
Naltrexone is an opioid antagonist, used primarily as
searches of the National Coronial Information System
a maintenance drug to aid opioid abstinence. Overdose
(NCIS). The NCIS is a regularly updated electronic
rates associated with naltrexone have been less well
database allowing access to all coronial cases in
documented than with methadone and buprenorphine,
Australia . Between 2000 and 2003, inclusive, an
perhaps because the greatest risk occurs after the
estimated 88% of a total of 66 659 coronial cases
cessation of treatment. While compliant with naltrex-
nationally were closed coronial cases (cases no longer
one, the effects of any opiates administered are blocked
under coronial investigation), and so were able to be
or reduced substantially . The primary cause of
used in this analysis (NCIS, unpublished data).
naltrexone-related death is by opioid overdose after
National registration data were used for the number
cessation of naltrexone treatment . Such deaths are
of buprenorphine and methadone treatment episodes.
unlikely to have naltrexone detected in post-mortem
As naltrexone is only available privately for the
toxicology, and only the mention of recently ceased (or
treatment of opioid dependence and registration data
non-compliant) naltrexone treatment identifies the
are not kept, the number of private prescriptions of oral
death as naltrexone-related. Less commonly recognised
naltrexone and expert clinical and research experience
causes of naltrexone-related death include fatal opioid
 of the typical naltrexone treatment retention were
overdose during naltrexone treatment , and death
used to calculate the number of naltrexone treatment
from a severe adverse reaction to naltrexone .
episodes. Mortality relating to unregistered forms of
There has been limited comparative work examining
naltrexone, such as depot formulations, was not
mortality rates across these three pharmacotherapies for
opioid dependence. Higher rates of opioid overdose
Mortality rates were calculated using: (a) a crude rate
(mainly non-fatal) in naltrexone subjects compared to
of deaths per 1000 treatment episodes and (b) a
methadone and buprenorphine subjects was noticed in a
stratified rate of deaths per 100 person-years at high
group of Australian studies . Subjects leaving naltr-
or low risk of death. All deaths were classified as
exone treatment had an overdose rate eight times that of
occurring in either the high- or low-risk period of death;
subjects leaving agonist treatment, and naltrexone
high-risk period deaths occurred if the date of death was
recipients were six times more likely to experience an
recorded as being within 2 weeks after the cessation of
overdose out of treatment than in treatment. Three of
naltrexone treatment episode or in the first week of
the 27 overdoses proved fatal . Another Australian
methadone or buprenorphine treatment.
study reported higher rates of non-fatal overdose in
Deaths during naltrexone treatment or after the first
naltrexone recipients compared to opioid agonist treat-
week of methadone or buprenorphine treatment were
classified as occurring during the low-risk period.
There has been no epidemiological work completed
Deaths where the timing was uncertain were classified
to examine rates of mortality related to these treatments
in the low-risk period of death and deaths occurring
Mortality related to pharmacotherapies for opioid dependence
more than 2 weeks post-treatment cessation were not
Methadone treatment was associated with a mortality
considered to be related to the treatment. Treatment
rate of 3.0 per 100 person-years during the high-risk
episodes were considered to have ended if the patient
period (first week of treatment) and 0.34 per 100
had formally left treatment at the time of their death.
person-years during the period of low risk (the
Using a mortality rate of deaths per person-years at risk
remainder of the treatment episode). Buprenorphine
reduces any bias caused by differing treatment reten-
mortality rates were not calculated using this method
tion between the three pharmacotherapies, as retention
due to the low number of deaths detected. Naltrexone
has been shown to be longer in methadone and
was associated with a mortality rate of 22.1 per 100
buprenorphine than in naltrexone .
person-years during the period of high risk (2 weeks
The significance of the difference in mortality rates
post-treatment), and one per 100 person-years during
was tested using Poisson regression models using SAS
the period of low risk (during treatment). Mortality
estimates and their 95% confidence intervals areincluded in Table 1.
Naltrexone subjects 2 weeks post-treatment (high-
risk period) had 7.4 times the risk of dying than
Searches of the NCIS revealed 282 methadone, one
methadone subjects in their first week of treatment
buprenorphine and 32 oral naltrexone-related deaths
(high-risk period). This risk was highly significant
during 2000 – 03 in Australia. Of these 258, one and 15
(p 5 0.0001, 95% CI: 4.6 – 11.5). Naltrexone subjects
deaths, respectively, met the criteria for ‘known’
during treatment (low-risk period) have 2.8 times the
methadone-, buprenorphine- and naltrexone-related
risk of dying than methadone subjects in the post-
deaths. This includes where the drug in question is
induction treatment period (low-risk period). This risk
mentioned as a cause of death in the coronial or autopsy
approaches significance (p ¼ 0.055, 95% CI: 1.3 – 5.7).
document, an opioid overdose within 2 weeks ofcessation of treatment or an opioid overdose where the
person is known to be in current treatment with the drugin question. A more detailed description can be found in
Deaths related to methadone, buprenorphine and
. According to national records, an estimated 102
naltrexone have occurred in Australia, and clear
615 episodes of methadone and 49 948 episodes of
differences in risk were observed. Whether estimated
buprenorphine treatment occurred in Australia during
as deaths per 1000 treatment episodes or per 100
that time. A total of 6337 private naltrexone prescrip-
person-years of high risk, the mortality rates for
tions were filled during 2000 – 03, each providing
naltrexone treatment were significantly higher than
medication for 1 month. Assuming mean treatment
those for methadone treatment (p 5 0.0001). Our
retention of 2 months, the number of oral naltrexone
methadone mortality rate of 3.0 deaths per 100
treatment episodes during this time was 3169.
patient-years is comparable to the 7.4 deaths per 100
The crude estimated mortality rate was 2.7 deaths
patient-years obtained by other researchers  in the
per 1000 episodes for methadone, 0.02 per 1000
initial high-risk period of treatment. Our buprenor-
treatment episodes for buprenorphine and 10.1 per
phine mortality rate of 0.02 per 1000 episodes can be
1000 treatment episodes for naltrexone. Naltrexone
compared to the French estimate of 0.24 per 1000
subjects had 3.7 times the mortality risk compared to
patients  and 2.5 per 1000 patients in the NEPOD
methadone subjects, a highly significant difference
studies . As only a single death in buprenorphine
(p 5 0.0001). With 95% confidence, the true relative
patients was noted in both this and the NEPOD
risk falls between 2.5 and 5.2 times higher than
studies, caution should be used when comparing rates
and significant differences in buprenorphine mortality
Table 1. Mortality rates per 1000 treatment episodes and per 100 person-years of exposure (stratified into periods of high and low risk of
to methadone and naltrexone treatment were not
that naltrexone implants carry a mortality risk. Nal-
trexone implant deaths may be more difficult to identify
The naltrexone-related mortality rate during treat-
than oral naltrexone deaths due to poor reporting of the
ment (one per 100 person-years) is very similar to the
presence of an implant at autopsy . Future work
overdose mortality rate for non-treated opioid depen-
needs to examine this issue carefully.
dent subjects of 0.9 per 100 person-years , suggest-ing that naltrexone offers little benefit in terms of
mortality risk. In the high-risk period after treatmentcessation, naltrexone-related mortality increased to
22.1 per 100 person-years, a rate clearly elevated
[28,29,34,36,46] have been accompanied by concerns
compared both to other pharmacotherapies and also
about the inability to monitor overdose deaths after
to active, dependent heroin use . The NEPOD
naltrexone treatment cessation . Both inadequa-
studies reported a naltrexone mortality rate of 4.8
cies in the data and assumptions in calculating the
deaths per 100 person-years after treatment cessation
mortality rates have the potential to bias, in particular,
. The lower mortality rate in these studies could be
our estimates of naltrexone mortality. First, identifying
partially a reflection of standardised treatment proto-
naltrexone-related deaths is difficult. Not only do
cols and intensive monitoring present in the research
naltrexone-related deaths rarely have naltrexone de-
rather than the general clinical setting. Mortality rates
tected in post-mortem toxicology, they rely on a past
following naltrexone treatment can also be compared to
episode of naltrexone treatment being recorded in
mortality in other reportedly opioid-abstinent situa-
coronial databases, something not conducted system-
tions, such as shortly after release from prison. The rate
atically in Australia. We were limited to keyword
of five deaths per 1000 prisoner releases in the 2 weeks
searching of the coronial database and so relied on
following release in a Scottish study  is lower than
correct spelling of the search terms in the files. For
our crude estimate of 10.1 deaths per 1000 treatment
this reason we believe we may have underestimated
the number of naltrexone-related deaths using the
The mortality rates we have found are plausible given
both the pharmacology of these drugs and previous
research [16,29,30,34]. Naltrexone is a treatment that
prescriptions of naltrexone were for opioid dependence
reduces tolerance to opioids, and reduces opioid effects
treatment. If we assume that half of opioid-dependent
during treatment. Buprenorphine and methadone, in
patients were also alcohol-dependent  and so
contrast, provide tolerance to all other opioids during
eligible for a public prescription, the number of
treatment. It is not surprising, then, that there is a
treatment episodes would be increased by 50%,
higher potential for more deaths to occur post-
reducing the naltrexone mortality estimate by a factor
of two. Thirdly, the mean length of a naltrexone
Retention in naltrexone treatment is poor: approxi-
treatment episode was estimated by a number of
mately one-third of subjects remain in naltrexone
clinical experts. Longer mean retention in treatment
treatment after 3 months [12,35]. The mortality risk
would elevate the naltrexone-related mortality.
associated with naltrexone treatment is of particular
Our selection of the first week of methadone
concern, considering the dangerous combination of
treatment as the period of high risk was influenced by
poor naltrexone compliance and sporadic heroin use
the limitations of the data and previous research .
This does not necessarily imply that the high-risk
It should be noted that naltrexone treatment may be
period does not extend to the first 2 weeks of treatment,
a useful option in some well-motivated patient sub-
as discussed by other authors [16,48]. No additional
groups, such as medical professionals [27,38], with
deaths were noted in the first 2 weeks of methadone
strong imperatives to remain abstinent. However, these
treatment compared to the first week. This may be a
subgroups represent the minority of dependent opioid
reflection of a certain bias in the NCIS: the further
users, and successful abstinence attempts are not the
separated a death was from the commencement of
norm, even in the well-motivated subjects .
treatment, the less likely the timing of treatment was
Implant technologies have been proposed as alter-
noted as salient in the coronial records.
native methods for delivering naltrexone [40 – 44].
These are not registered for use in Australia, and due
pharmacotherapies include deaths occurring among
to a lack of data on the number of naltrexone implant
people using diverted medication. In the case of
recipients this study was unable to make estimates of
methadone, 53 deaths (19%) occurred among people
mortality rates related to naltrexone implants. How-
using diverted medication and 37% had an unknown
ever, three naltrexone implant-related deaths were
treatment status. As the level of diversion is likely to be
identified in the NCIS over the same period, suggesting
different between methadone and naltrexone, this
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