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| Journal of the New Zealand Medical Association,
11-February-2005, Vol 118 No 1209
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Opioid poisoning deaths in New Zealand
(2001–2002)
David Reith, John Fountain, Murray Tilyard
Opioids are amongst the most commonly implicated drugs in
poisoning deaths.1 This is related to the
respiratory depressant and sedative effects of opioids, in addition to their
potential for abuse. Opioids are also commonly used in the treatment of the
terminally ill, and other patients with comorbidities, who have an increased
risk of dying whilst under treatment. Opioids are also used in the treatment of
substance abuse, such as in methadone maintenance programs. Patients with these
conditions have a greater overall mortality than the general
population.2
Recently there has been renewed interest in the role of
dextropropoxyphene in opioid poisoning deaths.3
In England and Wales for the period 1997 to 1999, dextropropoxyphene-paracetamol
combination medicines accounted for 5% of all suicides and 18% of drug-related
suicides.3 Dextropropoxyphene was found in 7.5%
of medicolegal autopsy peripheral blood specimens in Sweden between 1992 and
1996.4 Previously dextropropoxyphene has been
described as having a disproportionate risk in comparison with prescription
volumes.5 The hazard may be increased in
patients with coexisting medical conditions such as renal
failure.6 The aim of the present study was to
investigate the rates of opioid deaths in New Zealand relative to the
utilisation of opioids.
MethodsDeaths from opioid poisonings
for New Zealand from 1 January 2001 to 31 December 2002 were identified from
chemical injury cases that are routinely collected for surveillance purposes by
the Institute of Environmental Science and Research (ESR) from the Coronial
Services Office (CSO) in Wellington. The data used in the present analysis were
current as of 28 January 2004.
From previous experience, there may be delay of over a
year in the reporting of deaths from coroners and it is estimated 90%–95%
of the poisoning deaths for 2002 were recorded by this date. Toxicology data
were obtained from ESR toxicology reports that were present in approximately 95%
of the coroner’s files. Where this toxicology report was present, all
substances detected were recorded in the chemical injury database with the
exceptions of ethanol (where the blood level was less than 20 mg/dL) and
lignocaine (a drug commonly given in resuscitation).
As the toxicological analysis did not usually analyse
heroin separately, the heroin deaths were included with the morphine deaths.
Whether the deaths were intentional (suicides or homicides) or unintentional
(accidents) was determined according to the report of the coroner. The substance
primarily involved in the fatality was determined using firstly the
cause/circumstance recorded by the coroner, and secondly the primary and
secondary substances identified in the ESR toxicology report.
Prescriptions for medicines containing morphine,
methadone, and dextropropoxyphene were identified from the PharmHouse database
from 1 January 2001 to 31 December 2002. The PharmHouse database is a subset of
the New Zealand Health Information System database and contains records of all
the claims for medicines dispensed within New Zealand. As codeine-containing
preparations are available over the counter in New Zealand, prescription data
were not obtained for codeine.
The records included the drug name, formulation,
strength, type of prescriber, and the prescriber’s New Zealand Medical
Council number. The data were imported into Stata® for data management to
enable tabulation of the prescription numbers by drug
type.7 Analyses were also performed using
defined daily doses (DDD) dispensed as the
denominator.8 The defined daily doses used
analgesia as the indication, and were 200 mg for dextropropoxyphene
hydrochloride, 300 mg for dextropropoxyphene napsylate, 100 mg for morphine, and
25 mg for methadone. Rates and their 95% confidence intervals were calculated
using the command ‘cii’ and the Poisson distribution in
Stata®.
ResultsThere were 92 poisoning deaths
involving opioids in New Zealand during 2001 and 2002 (Table 1). Morphine was
the most frequently reported opioid reported in poisoning deaths, but there were
almost as many methadone-related deaths.
Table 1. Opioid deaths for 2001–2002 compared
with usage (prescription volume or DDDs)
Methadone and morphine deaths were predominantly considered
to be unintentional with 28 of the 31 methadone deaths and 24 of 33 morphine
deaths coded as unintentional, compared to 6 of 16 dextropropoxyphene deaths and
2 of 12 codeine/dihydrocodeine deaths. Fifty-two (56%) of the deaths occurred in
males.
Sixty-two (67%) of the deaths occurred in the 25–44
year age group, 14 (15%) in the 45 to 64 year age group, 10 (11%) in the
15–24 year age group, and 6 (6%) in the over 65 year age group. There was
an increased frequency of methadone deaths on Monday, Friday, and Saturday,
compared with the other days of the week; no methadone deaths occurred on a
Wednesday. It was not possible to determine whether in each case the deceased
had been prescribed the opioid or had obtained the substance
illicitly.
Table 2. Usage of dextropropoxyphene, morphine, and
desxtropropoxyphene formulations (2001–2002)
DDDs=defined
daily doses; Cap=capsule; Tab=tablet; NA=data not available.
The most commonly prescribed formulation was
dextropropoxyphene 50 mg with paracetamol 325 mg (Table 2), accounting for 49%
of the analgesic opioid (dextropropoxyphene and morphine) prescriptions and 79%
of the unit doses. The total number of prescriptions indicates that
dextropropoxyphene was commonly prescribed in New Zealand during the study. When
analysed by prescriptions, the death rate was similar for dextropropoxyphene and
methadone, and both drugs had a lower rate of death than morphine (Table 1).
When analysed by DDDs, dispensed dextropropoxyphene had the lowest rate of death
followed by methadone, then morphine.
A total of 9255 prescribers issued at least one prescription
for an opioid: 1064 prescribers issued at least one prescription for
dextropropoxyphene, 7692 issued at least 1 prescription for
dextropropoxyphene-paracetamol, 7172 issued at least 1 prescription for morphine
sulphate, and 2779 issued at least 1 prescription for methadone.
The median number of prescriptions per prescriber of
dextropropoxyphene 100 mg was 3, with a range of 1 to 342. The median number of
morphine prescriptions was also 3 with a range of 1 to 1371. There was marked
skewing of the prescription volume per prescriber for
dextropropoxyphene-paracetamol. The top 5% of prescribers by volume were
responsible for 44% of the dextropropoxyphene-paracetamol prescriptions, while
the top 1% of prescribers were responsible for 17% of prescriptions and the top
0.1% of prescribers were responsible for 4.5% of prescriptions. The top 5% of
prescribers by tablet number were also responsible for prescribing 45% of the
tablet volume for dextropropoxyphene-paracetamol.
DiscussionDextropropoxyphene has previously
been associated with a disproportionate rate of poisoning deaths in relation to
prescription volume.3,5 The mode of death in
dextropropoxyphene poisoning is a combination of respiratory and central nervous
system depression, resulting from opioid effects; and cardiac arrhythmia,
secondary to QT prolongation.9 Whilst tolerance
may develop to the opioid effects, this would not be expected for the QRS
prolongation. Hence patients who are on high doses of dextropropoxyphene, or are
abusing dextropropoxyphene, may be at risk of cardiac arrhythmia. The majority
of these deaths are reported as suicides, but the rate of accidental death is
unexpectedly high and may be
underestimated.10
Dextropropoxyphene has little advantage over paracetamol,
and does not confer any benefit in combination with paracetamol, in clinical
trials.11 Although the present study was not
able to measure the prescribing of paracetamol-codeine formulations, there were
fewer deaths attributed to codeine over the time period of the study.
Paracetamol-codeine preparations would be expected to have a better risk benefit
profile than dextropropoxyphene-paracetamol, and should be preferred, except
where there exists an allergy to codeine, or lack of response to codeine.
Patients who are deficient in CYP2D6 (the enzyme that biotransforms codeine to
morphine) may show no analgesic response to codeine and it may be preferable to
prescribe morphine to these
patients.12
Preliminary findings also suggest that by reducing the
availability of dextropropoxyphene-paracetamol, poisoning deaths due to
dextropropoxyphene-paracetamol can be reduced, but there is not necessarily a
reduction in overall suicide mortality.13,14
However some of the dextropropoxyphene deaths appear to be accidental and
restricting the availability of dextropropoxyphene may result in a decrease in
these deaths.10 A difference in the
representation of dextropropoxyphene in poisoning deaths in Scandinavian
countries has previously been attributed to differences in availability of
dextropropoxyphene.15
Methadone has previously been reported as a disproportionate
contributor to poisoning deaths in New
Zealand.16 This may be due to the practice of
providing ‘takeaways’ for multiple doses that may be consumed as a
single dose, and/or the illicit provision of these ‘takeaways’ to
persons for whom they were not prescribed. Another factor may be the relatively
low availability of heroin in New Zealand, reflected in a proportionately
greater usage of methadone. The mode of death in methadone-related deaths is
thought to be primarily respiratory depression, although in high doses torsade
de pointes may occur.17
A contributing factor may be the time delay in achieving
peak effect, which may be 4 hours in oral ingestion and 1 to 2 hours after
subcutaneous or intramuscular administration.18
A significant proportion of the deaths appear to occur in naïve users,
through the use of ‘diverted’
methadone.19 An inexperienced user may be
falsely reassured by the lack of effect experienced immediately after
administration, and doses/plasma levels tolerated by experienced users may be
lethal to a naïve user. Similarly, a period of abstinence in an experienced
user may increase the risk of fatal opioid overdose due to loss of
tolerance.20, 21
The association of ‘takeaways’ with an increased
rate of methadone-related deaths and diversion to naïve users has also been
noted in Scotland.22 An increased rate of
methadone-related deaths has also been noted on Saturdays and Sundays (but not
Fridays), which is possibly related to pharmacy closures on
Sundays.1 With improved surveillance of
methadone maintenance programs, this hazard has been ameliorated, with a
consequent containment of methadone-related
deaths.22 Hence, the practice of supplying
‘takeaway’ methadone doses in New Zealand appears to be a hazard and
should be reviewed.
Indeed, a more robust monitoring of both the prescribing and
dispensing of methadone could contribute to a decrease in methadone poisoning
deaths. However, greater access to methadone maintenance programs appears to
decrease overall opioid-related mortality and such programs should be maintained
with appropriate controls.23
Another contributor to opioid deaths is co-ingestion of
ethanol and other sedative agents.2 Opioids
induce sedation via a different receptor mechanism to ethanol, benzodiazepines,
and other sedatives, hence the effects of co-ingestion are additive. Therefore,
caution should be exercised when prescribing opioids to patients with a history
of ethanol abuse, or who are medicated with benzodiazepines.
The limitations of the present study include: an inability
to measure illicit supply of opioids, an inability to determine intent, an
inability to distinguish between heroin and morphine, and an inability to
determine whether the opioids were diverted or prescribed. The DDD used were for
analgesia, but the patients for which they were prescribed may have been
tolerant to opioids and have therefore received higher doses. In addition,
patterns of illicit drug use in New Zealand may differ from other countries in
the region.
In New Zealand, there is a relatively high utilisation of
methadone and morphine relative to illicit heroin use. This can be related to
the production of morphine from codeine, obtained from commercially available
codeine-containing products.24 Hence
morphine-related deaths in New Zealand may be due to illicitly produced
morphine, in addition to illicit heroin, rather than morphine prescribed for
therapeutic uses. New Zealand may also have a relatively high rate of
amphetamine use compared with illicit opioid
use;25 so it may not be possible to extrapolate
findings from New Zealand to other countries.
ConclusionsRestrictions in the availability of
dextropropoxyphene, and increased monitoring of prescription and dispensing of
methadone, should be considered in order to reduce deaths due to opioids in New
Zealand.
Author information:
David M Reith, Senior Lecturer, Dunedin School of Medicine, University of Otago,
Dunedin; John S Fountain, Medical Toxicologist, New Zealand National Poisons
Centre, University of Otago, Dunedin; Murray Tilyard, ‘Elaine Gurr
Professor of General Practice’, Dunedin School of Medicine, University of
Otago, Dunedin
Acknowledgements: We
thank Rebecca McDowell and Jeff Fowles (Health Information Analysts, Population
and Environmental Health, Institute of Environmental Science & Research) for
provision of data.
Correspondence: Dr
David Reith, Senior Lecturer, Dunedin School of Medicine,
3rd Floor Children’s Pavilion,
Dunedin Hospital, Great King Street, Dunedin. Fax: (03) 474 7817; email: david.reith@stonebow.otago.ac.nz
References:
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