av Birgitta
Jonasson and Ulf Jonasson
in collaboration with the Swedish National Board of Forensic Medicine
Contents
Foreword by the National Board of Forensic
Medicine
Authors’
preface to the English edition
CHAPTER 1
Introduction
A short summary of the content of this
report
The organisation and duties of forensic
medicine in Sweden
Results in summary
Conclusions
CHAPTER 2
Dextropropoxyphene
– field of application and toxicity
Background and field of application
Pharmacokinetics
and pharmacodynamics of DXP
Toxicity
of DXP
Fatal
DXP poisoning – suicide or accident?
CHAPTER 3
International
experiences and measures taken
DXP in the United States
DXP
in the United Kingdom
DXP
in Denmark
DXP
in Norway
DXP
in Sweden
An
Australian contribution
Summary
CHAPTER 4
Dependence on DXP
The scheduling of narcotic drugs
CHAPTER 5
Summary,
discussion and conclusion
Analgesic dependence among chronic pain
patients
The prevalence of DXP and fatal DXP
poisoning among forensic autopsies
DXP and alcohol
The classification of the manner of death
in fatal DXP poisoning
Unmixed and combined DXP preparations
Age and kind of preparation in fatal
poisoning
DXP in individuals suspected of driving
under influence
The analgesic effect of DXP according to
meta-studies
Summary
APPENDIX
Appendix 1 Eight studies on
dextropropoxyphene
Appendix 2 References
Foreword by the National Board of Forensic Medicine
Authors’ preface to the English edition
The interest in examining the analgesic preparation
dextropropoxyphene (DXP) and its side-effects in respect to dependence and
fatal poisonings first emanated from our experiences from teaching in early
detection of alcohol and drug problems. On several occasions physicians and
other professionals reported that they had seen patients abuse analgesics such
as Distalgesic, and that some of them had died suddenly and unexpectedly after
having combined alcohol with these pills. These individual referents all
considered that DXP was a serious problem that needed attention.
Against this background we started a
project at the Department of Forensic Medicine at Uppsala University, under the
supervision of Tom Saldeen, MD, PhD, professor and chairman of the department.
The project has led to eight scientific papers (1-8), all published in
international scientific journals, and one doctoral thesis (9). A second thesis
will be presented in March 2001. Unfortunately, results of scientific research
are mostly slow in reaching the public. Scientific publications are often read
only by a handful of individuals who are interested in that particular subject
or journal, and otherwise they are placed on some bookshelf and remain unread.
Early in the project we found a
considerably high rate of fatal poisonings due to DXP, both suicidal and
accidental. We then became aware of the fact that if human lives were to be
saved, it would be necessary to inform the society outside the academic world
of the results of the research. We considered it important to inform both the
prescribing physicians and the users of DXP about the risks of the most
frequently prescribed analgesic preparation in our country. It seemed urgent
that we should reach not only abusers but also the ordinary users, since both
categories are at risk of becoming intoxicated, all too often with a fatal
outcome.
The National Board of Forensic Medicine,
which has supported us financially, agree about the importance of disseminating
our results and has edited this report, which is intended among others, for
general practitioners, journalists, politicians and the general public. The
Swedish version of the report has attracted much attention and so far has been
printed three times.
Since we have reason to believe that the
problem of constantly high rates of DXP fatalities is not limited to Sweden, we
hope that the translation of this report into English will constitute a useful
contribution to the debate in other countries. Reports have indicated that
dextropropoxyphene-related deaths are a persistent problem in the United
Kingdom (10), in Australia (11), in New Zealand (12) and in the USA (13). In
all countries where DXP is frequently prescribed, a rate of fatal DXP poisoning
comparable to that in Sweden can be expected. When related to the population
and assuming similar conditions, the number of deaths each year would be about
5,000–7,000 in the United States, about 1,000–1,200 in the United Kingdom,
about 300–400 in Australia and about 60-70 in New Zealand.
Acknowledgements:
We wish to express our gratitude to our supervisor,
Professor Tom Saldeen. We also thank the National Board of Forensic Medicine
for financial support and encouragement in the project and for editing the
report of our collected research.
We are also grateful to the Swedish Poison
Information Centre, which prior to our studies had recognised the risks of DXP
and seriously shared and supported our concern about the constantly high rate
of fatal poisonings caused by this preparation. We are indebted to the National
Corporation of Swedish Pharmacies, which has supported us with information on
the prescribing of DXP preparations during the study years, and the National
Board of Health in Denmark, which gave us the opportunity to read all documents
regarding the process leading to restrictions of DXP prescription included in
their DXP dossier.
Finally, we want to dedicate this book to
all the 1,600 persons who were known to be victims of fatal DXP poisoning
during the years 1992 - 1999. Their tragic deaths have given us knowledge of
the serious risks of our most frequently prescribed analgesic preparation. It
is our hope and expectation that this knowledge will contribute to saving lives
in the future.
Uppsala, Sweden Picture
January 2001
Birgitta Jonasson
Fully certified psychologist, fully certified
psychotherapist,
Doctor of Medical Science
Ulf Jonasson
Journalist, graduate student in Public Health
CHAPTER 1
Introduction
Dextropropoxyphene (DXP) is one of the most frequently
prescribed analgesic compounds in Sweden today and it is recommended to
patients with moderate to serious pain. There are seven preparations containing
DXP on the Swedish market; in three of them DXP is the sole analgesic
ingredient, while four of them are combinations of analgesics. In Distalgesic,
for example, paracetamol is also included. In 1996 the sale of DXP preparations
was 14.4 defined daily doses/1,000 inhabitants during a 12-month period (DDD).
A short summary of the content of this report
Chapter 2 gives a general background of the
production of DXP in the 1950s and describes how it quickly gained world-wide
popularity. Soon after its introduction it was reported, however, that the
margin between the therapeutic and toxic doses was small, and in chapter 3 the
discussions in the USA, the United Kingdom and the Scandinavian countries
following this discovery are presented. We have paid special attention to the
process leading to restriction of the prescribing of DXP in Denmark, contrasting
this with the lack of a similar debate in Sweden. At the end of this chapter
the classification of the manner of death in fatal poisoning is considered. How
does the physician establish the intent of the deceased in cases of
self-inflicted deaths?
In chapter 4 dependence on therapeutic
drugs is discussed and the scheduling of narcotic drugs is described. When DXP
was introduced, it was claimed that unlike morphine and some of the more potent
analgesics it caused little or no tendency to addiction. However, soon after
its introduction case reports showed that just like other opioids, DXP could
lead to dependence and abuse.
Our studies are summarised in chapter 5.
We first investigated analgesic use disorders among chronic pain patients at a
rehabilitation clinic in Sweden. There were indications that some patients did
become dependent on analgesics and in 1992 a new admission routine was
initiated, whereby all patients were interviewed concerning their drug use. The
investigation showed that patients with chronic pain are at considerable risk
of developing DXP use disorders, even when on ordinary medication. Since we had
been told that some persons had died unexpectedly when consuming DXP, it seemed
natural to continue to examine this drug in the context of forensic medicine.
The eight studies summarised in chapter 5
are presented in more detail in Appendix 1 for the benefit of any readers who
would like to know more about the methods, the results and the discussions in
each study. For further analysis we refer to the original published articles.
All references are found in Appendix 2.
Below we will give a brief description of
the forensic medicine activity in Sweden and the bases of our autopsy
investigations.
The organisation and duties of forensic
medicine in Sweden
The primary task of forensic medicine is to
investigate deaths that are suspected to be unnatural and persons involved in
suspected crimes of violence. The findings and conclusions are presented in
legal certificates and form a basis of decisions by the police, prosecutors and
courts. The vast and solid experience of forensic medicine has also contributed
to the work of prevention of crime, injury and disease conducted by other
authorities and organisations, as well as to the efforts of finding the causes
of sudden and unexpected deaths.
The organisation of the medico-legal
examiner system in Sweden is influenced by the continental system, which is a
common model in large parts of Europe. All autopsies in cases of deaths
suspected to be unnatural are conducted on behalf of the judicial bodies,
mainly the police. Since 1991, all medico-legal work in Sweden is carried out
at six departments of forensic medicine that answer to the National Board of
Forensic Medicine. The National Board is also responsible for the fields of
forensic chemistry, forensic genetics, and investigational forensic psychiatry.
About 90,000 people die in Sweden every
year. Of interest to forensic medicine are primarily deaths due to accidents,
crimes and suicide, i.e. cases of unnatural death. The frequency of autopsies
has gradually decreased, from about 40 per cent in 1980 to 20 per cent in 1995.
About 70 per cent of the autopsies are performed within the medical service,
while the remaining 30 per cent (between 5,000 and 6,000 per year) are
medico-legal autopsies undertaken at the departments of forensic medicine. The
medico-legal autopsies include almost all deaths due to homicide, manslaughter,
other violence, and suicide. In addition, the departments of forensic medicine
deal with more than 90 per cent of the traffic deaths and about half of all
other fatal accidents.
A forensic chemistry analysis is required
in about 90 per cent of all medico-legal investigations of death. The purpose
of these analyses may vary from screening for chemical substances that might
explain a case of death, to exclusion of the presence of alcohol, prescription
drugs, or other substances. Prescription drugs, primarily sleeping pills,
sedatives and analgesics, are commonly found in connection with suicide and
deaths from undetermined causes.
The results obtained in the fields of
forensic medicine and forensic chemistry provide a useful source of data on
unnatural deaths as well as on unexpected natural deaths, and a computer-based
system for assignment management (RättsBase for forensic medicine and ToxBase
for forensic chemistry) has been developed and put into operation. The two
databases contain all assignments since 1992 and constitute valuable resources
for research and development work, not only in the forensic sciences but to a
great extent also for researchers within other areas of society, such as
universities and public authorities and organisations (14).
RättsBase and ToxBase made it possible for
us to examine all the medico-legal autopsy cases in Sweden from 1992 to 1996,
thus giving us results on a national level. We have since updated the
investigation to include all the autopsy cases up to 1999. Beside the results
from the published studies we will therefore complete this presentation with
the results from the updating.
Results in summary
The prevalence of DXP in the peripheral blood of the
deceased increased by 35% from 1992 (6.8%) to 1997 (9.2%). In 1998 and 1999 a
tendency to a reduction was noted (8.3% and 8.1% respectively). DXP was the
single preparation causing the incomparably largest number of fatal poisonings
in Sweden during the study years. DXP caused or contributed to death in a total
of 1,592 cases during the period 1992 to 1999, i. e. in about 200 fatal
poisoning cases per year (range 158-227).
Middle-aged men, habitual or social
drinkers, on medication for pain, are most prone to combine DXP and alcohol and
are most liable to become victims of accidental poisoning due to a combination
of DXP and alcohol. About 30 men and 10 women died accidentally every year of
the study period of this combination.
Unmixed preparations were over-represented
among fatal poisonings where DXP caused or contributed to death, compared with
preparations containing DXP combined with other analgesics. Among fatal
poisoning cases due to DXP, antidepressants or sedatives, DXP predominated
among younger people compared with the other drugs.
Accidental DXP fatalities were
underestimated. The alternative to a report of suicide on death certificates in
these fatalities has become an undetermined manner of death, thus reducing
judgements of the deaths as accidents to a minimum. As discussions of suicide
rates often include the undetermined cases, there will most certainly be a
considerable over-representation of suicide in the case of DXP. And this in
turn will increase the risk that knowledge of the high toxicity of DXP will not
reach the population consuming this drug.
Conclusions
In order to save a considerable number of human lives
each year in our country, we propose strict regulations in the prescribing of
DXP, as it seems absolutely necessary to limit the availability of the DXP
preparations. The combination of liability to addiction and high toxicity makes
DXP especially dangerous, since one of the most important criteria for being
dependent is loss of control of the amount taken. As DXP can even be lethal
within the therapeutic range when combined with alcohol or sedatives, it may
become a death trap not only to those who misuse, but also to ordinary users of
this analgesic.
The natural thing would be to remove DXP
completely from the market and to replace it with preparations that are less
dangerous when it comes to the risk of poisoning as well as the risk of
dependence. Today alternative analgesics are available for prescription to the
category of patients at present receiving DXP.
CHAPTER 2
Dextropropoxyphene –
field of application and toxicity
Background and field of application
Opium
was known to have therapeutic effects on the human body as early as 5,000 years
ago among civilisations in the areas of the Euphrates, the Tigris and the Nile.
As opium had a depressant effect on what is now known as the central nervous
system (CNS), it was used as an analgesic drug. In the beginning of the 19th
century chemists discovered that crude opium contained about 20 different
alkaloids, which are chemical compounds existing naturally in the vegetable
kingdom and which often have strong effects on the human organism. The most
important of these alkaloids are morphine and codeine. Morphine is the most
powerful analgesic existing today and it also creates a psychological sense of
well-being, i. e. euphoria.
In the year 1874, diacetylmorphine – in daily language heroin
– was for the first time produced from morphine. Heroin, which was first
recognised as a problem in Sweden as late as in 1975, is a semisynthetic drug,
while methadone and DXP are completely synthesised, with effects resembling
those of morphine, only weaker (15).
DXP is chemically similar to methadone and pharmacologically
to codeine. It was first synthesised in 1953 (16). At that time there was a
need for an analgesic that was free from the side-effects of other narcotic
analgesics, namely the development of tolerance, which presages a liability to
addiction, and respiratory depression, which has serious consequences in
general anaesthesia and obstetrics.
In 1958 DXP was presented in JAMA as Dextro Propoxyphene
Hydrochloride - under the section of New and Nonofficial drugs (17). It was
stated that unlike morphine and some of the more potent analgesics it produced
no respiratory depression after therapeutic doses, that its addiction liability
was little or none and that its toxicity was low and the margin of safety
adequate.
Pharmacokinetics and pharmacodynamics of DXP
DXP
is rapidly absorbed after oral administration and the peak plasma level is
usually attained within one hour of a single oral dose. However, since DXP
undergoes marked first-pass biotransformation, only a small proportion of the
absorbed dose enters the circulation in unchanged form. The remainder of the
drug is metabolised to norpropoxyphene. The elimination half-life of DXP is 12
hours, but that of norpropoxyphene is three times longer, 36 hours. With
repeated administration of DXP, accumulation leads to plasma concentrations
that are at least 500% higher than with single doses, and consequently the
elimination half-time may be substantially prolonged. It has been found that
alcohol reduces the first-pass biotransformation of DXP, so that the
availability of the administered dose may be enhanced by 25-50% (18-21).
Toxicity of DXP
DXP
preparations immediately became very popular, but a short time after their
introduction evidence of high toxicity of DXP began to be reported. The first
report on a case of self-poisoning with DXP was published in 1960 (22), and
this was soon followed by other reports of acute overdoses of DXP, cases in
which the persons had survived (23-25).
In 1964 the first fatality was reported (26), a teenage girl
who died after ingestion of an overdose of DXP. The authors concluded that
although in normal doses DXP is well tolerated (according to the Department of
Forensic Chemistry the blood level of DXP after a therapeutic dose is 0.05-0.75
µg/g), in excessive doses it possesses a malignant potential in terms of
central nervous system toxicity. In severe poisoning, rapid loss of
consciousness, respiratory depression, hypoxia, and ultimately cardiovascular
collapse appear to be the expected course.
In the 1960s it was discovered that the margin between
therapeutic and toxic doses was narrow and that the effects of DXP were
potentiated after intake of alcohol. When alcohol and other toxic substances
were absent, the minimal fatal concentration of DXP in the blood was found to
be 2-3 µg/g (3-4 times the therapeutic dose). When DXP was combined with
alcohol, death would occur at blood concentrations as low as 1-2 µg/g, in some
cases as low as 0.2 µg/g. It was
shown that there is a high risk of death if 20 or more Distalgesic tablets,
each containing 32.5 mg DXP and 325 mg paracetamol are ingested, and that as
few as 6 to 15 tablets can lead to lethal consequences when potentiated by
alcohol. Further, it was shown that
synergism also exists between DXP and barbiturates (27-31).
Fatal DXP poisoning – suicide or
accident?
When
a person dies of poisoning it is the task of the forensic medical physician to
decide whether the manner of death was suicide
or an accident. The manner of death
is classified in accordance with the International Classification of Diseases
(ICD), which also includes a classification of injuries and causes of death.
The revisions of ICD have included some changes in the way in which
self-inflicted deaths should be classified. According to the seventh revision,
ICD-7 (1958), self-inflicted deaths were to be regarded as suicide if it could
not be proved that the death was unintentional. When the eighth revision,
ICD-8, was introduced in 1968, an “undetermined” manner of death was added as
an alternative to suicide in the classification of self-inflicted deaths. From
this it could be understood that self-inflicted death should not be considered
as suicide unless the certifier was able to establish that the deceased
intended death (32). ICD-9 and ICD-10 follow a similar approach (33).
The rapid death in DXP poisoning, the narrow margin between
therapeutic and toxic doses, and the potentiation of DXP when mixed with
alcohol may lead to difficulties in assessing the intent of the deceased in
cases of self-inflicted fatal poisoning, and in classifying death as
accidental, suicidal or undetermined. There is no agreement on valid rates of
suicide or accidents associated with this drug. A suicide rate of 50-60% has
frequently been reported, while the accident rate has varied between 25% and
49% (34-36).
(Picture:
Suicide? Accident?)
CHAPTER
3
International
experiences and measures taken
There
has been considerable scientific documentation of DXP toxicity in some parts of
the world since the 1970s, and a survey of the discussion on this subject in
the United States, the United Kingdom and Scandinavia, and of the measures
taken to prevent DXP intoxication, is presented below.
DXP in the
United States
Early
in the 1970s warnings about the risk of DXP toxicity and about the potentiating
action of alcohol on the DXP effect were issued in the USA on the bases of
clinical reports (37). It was concluded that physicians should be alerted to
the potential deleterious effects of indiscriminate use and abuse of DXP, and
should warn their patients not to drink alcohol when taking DXP. It was
recommended that physicians should observe extreme caution when prescribing DXP
to young people.
In extensive surveys it was found that the number of deaths
involving DXP was increasing each year, and at a faster rate than the total
drug deaths. Deaths attributed to suicide, as well as those judged to be
accidental deaths and undetermined deaths had increased (35, 38-40). DXP,
according to these studies, did not appear to be a paediatric problem. Nor did
the deceased persons belong to the illegal drug abuse population or have any
particular propensity for the use of heroin or narcotics. Rather they
constituted a particular medical population of those who misuse prescription
drugs and alcohol. Almost all of them received a wide range of prescription
drugs, particularly tranquillisers, which they often misused by
self-medication, multiple drug ingestion, and combining alcohol with their
medication.
The reports of fatalities due to DXP led to an information
campaign in 1978-80 undertaken by the US Food and Drug Administration (FDA) and
the drug’s manufacturer through mailed warnings, face-to-face education of
prescribers, press- releases, and labelling changes. The goal was to reduce simultaneous
use of DXP and alcohol or other CNS depressants, to reduce the prescription of
refills, and to get physicians to stop prescribing DXP for patients at risk of
abuse and misuse.
Trends in prescribing and deaths related to DXP overdose
before and after this campaign were analysed by Soumerai and collaborators
(14). They found that a pre-existing downward trend of about 8% per year
continued during the warnings, but halted after them. The no-refill
recommendations had no effect on the refill rates. They also noted that the
overdose death per DXP prescription had remained about constant since 1979, and
considered that stronger, more sustained regulatory or educational measures had
to be implemented to achieve any sharper reductions in the misuse of the drug.
Further, they suggested that the wide extent of DXP use is mainly due to its
overall popularity in relation to competitive products, probably largely on
account of effective marketing activities. One example of these activities is
described in their report:
As FDA had no ongoing physician education programme of its
own, it requested that the manufacturer of DXP should revise the drug labelling
and conduct both a mailed and a person-to-person educational campaign. Eli
Lilly and Company sent a mailed warning message to 145,000 physicians, but when
it came to the face-to-face education an investigation conducted by an FDA
official showed that Eli Lilly did not fulfil this commitment. It was only in
less than 10% of the "face-to-face educational occasions" that the
detailers conveyed suitable information on the new warnings; while over 75% of
the detailers left free samples of DXP products on those particular occasions.
The FDA official quoted several verbatim messages from Lilly detailers recorded
by physicians. “Darvon and Lilly won FDA battle”, “Safe in spite of Nader
report”, “OK by the Drug Commission”, “Few if any side effects”.
(Picture: “And here you are, some free samples”)
Today
DXP is among the top ten drugs reported by medical examiners to occur in deaths
due to drug abuse.
DXP in the
United Kingdom
In
the United Kingdom it was claimed in the early 1970s that many doctors were
unaware of the danger of DXP in overdose and that the problem of this drug in
the UK was not fully appreciated. Some clinicians found that deaths occurred
very rapidly, suggesting that the narcotic effects of DXP predominate, and that
this might explain the sparsity of clinical reports (41).
During the 1980s there was a considerable discussion and
research on DXP in the UK (21, 30, 43-50). In 1980 Young and Lawson concluded
that no analgesics are devoid of danger when taken in overdose, but stated that
in DXP the evidence suggests that its dangers exceed its analgesic properties
(30). In 1987 the debate of the 1980s came to a close with a review by Lawson
and Northridge of the world-wide situation regarding acute overdose of DXP
(21). Among other aspects, they surveyed the effects of different preventive
measures adopted in various countries. Their final conclusion was that if
effective primary prevention was to be attempted by restricting the prescribing
of an analgesic, then alternative agents that were safer in both normal usage
and in overdose, and preferably no more expensive, had to be promoted. In the
mid-1990s the fact was established that DXP-related deaths were a problem that
persisted in the UK (10). As compound analgesic preparations containing DXP
were still widely prescribed and deaths due to DXP overdose were persistent,
the introduction of stricter prescription control and educational programmes
for users was proposed.
DXP in
Denmark
As
in the UK, reports of DXP poisoning began to appear in Denmark in the early
1970s. A rapid increase in fatal accidental DXP poisonings that was
proportional to the increased use of the drug was reported (51). It was pointed
out that DXP in the form of a slow-release preparation (Abalgin retard) was
especially dangerous, because of repeated dosage by patients attempting to
induce the therapeutic effect more quickly.
In 1982 the Danish National Board of Health sent a message to
all physicians to the effect that they should not prescribe DXP preparations to
known addicts. This led to a small decrease in the prescription rate (from 8.4
DDD in 1982 to 8.0 DDD in 1983) (52). The National Board of Health also started
to make enquiries in all cases of fatal DXP poisoning of alcohol and/or drug
abusers, and asked the prescribing doctor about the indication and dosing
instructions for the drug (National Board of Health, 1998).
In spite of the above-mentioned measures, reports of fatal
DXP poisonings continued to be published (53-60) and in the dossier at the
National Board of Health (54) DXP was now labelled “the killer drug”, quoting
one of the reports (55). In April 1988 the National Board of Health considered
total withdrawal of DXP preparations, but as it was concluded from an
investigation ordered by the Board that DXP preparations were regarded as a
valuable alternative to acetylsalicylic acid and paracetamol by some patients (61),
and since there were no satisfactory analgesic alternatives for patients with
moderate pain, strict prescription regulations were decided upon instead.
In July 1988 information was sent to all physicians in
Denmark to the effect that it was now obligatory that they should submit copies
of all prescriptions of DXP preparations for registration. The prescription
form for narcotic drugs was to be used, with only one preparation per
prescription. The national identity number of both the patient and the prescribing
physician should be recorded. Further, it was again emphasised that DXP
preparations should not be prescribed to alcoholics or drug addicts, but only
to patients without any mental disorders. DXP should not constitute first-hand
choice, before comparable analgesics had been tested.
The public attention drawn to the DXP problem by the National
Board of Health and finally the prescription regulations led to a decline in
the DXP prescription rate and in rate of deaths due to DXP during the late
1980s. The death rate from DXP poisoning decreased by 45% from 1986 to 1992,
while the DDD was reduced by 60% from 1985 to 1992 (62-65).
The measures taken in Denmark to reduce prescribing of DXP
and the DXP death rate were successful, but it seemed as if the heavier
narcotic medical compounds partly compensated for these declines. In Denmark
the legal prescribing of strong opioids is higher than in any other country in
the world after adjustment for size of population (66).
DXP in
Norway
In
Norway a warning concerning the risk of intoxication by DXP was sent to all
physicians in 1975 (67). In 1982 the regulations were strengthened, and DXP
came to be classified in the same group as morphine. A decline in the death
rate from DXP poisoning had already occurred in connection with the discussion
preceding the more stringent regulations (68). The DDD has been constant at 1.6
since 1990 (69). The present death rate for DXP poisoning is 4-8 cases per year
(70).
No other opioid has compensated for DXP, but generally the
use of analgesic drugs is lower in Norway than in many other countries. In 1995
the sale of analgesics in Norway amounted to 64% of that in Sweden and to 60%
of that in Denmark. The majority of the prescribed drugs were non-narcotic. The
narcotic drugs comprised 5% of the total use of analgesics (69).
DXP in
Sweden
In
Sweden only a few reports have been published on the subject of DXP since the
1970s. In a study in 1971 it was concluded that DXP may be fatal even in
moderate doses, that analgesic compounds seem to be associated with an
especially high risk, and that there is a risk of dependence with these drugs.
As the analgesic effect of DXP is not strikingly high, they suggested that
caution should be observed in the prescribing of these preparations, and that
the market should be cleansed regarding to the DXP compounds (71).
A literature survey undertaken to assess the risks of abuse
and poisoning due to DXP, based on 542 references concerning this drug, was
published in 1976 (72). The reviewers found that 112-160 fatal poisoning cases
due to DXP occurred every year in Sweden, and drew the same conclusions as in
the study mentioned above, namely that caution should be observed when
prescribing DXP. In view of the high toxicity, physicians should only prescribe
small amounts of the drug, and should not prescribe DXP to patients at risk,
for example alcoholics and drug addicts. The physicians should warn the
patients of the risk of taking alcohol together with DXP.
The prescription rate temporarily decreased during the last
years of the 1970s and nothing of the DXP discussions held in the USA, the UK
and the other Scandinavian countries, Denmark and Norway, during the 1980s was
reflected in Sweden. There was complete silence until 1993, when an increase in
the rate of deaths due to DXP from 88 in 1985 to 119 in 1990 was reported (73).
In 1985 the DXP fatalities constituted 64% of all analgesic poisonings,
compared with 72% in 1990. DXP was also found to be responsible for the largest
number of all fatal poisonings in Sweden during the years 1992–1995 (74).
In 1994 we started research on side-effects of DXP and in
1999 we summarised our research in the Swedish version of this report,
supported by the National Board of Forensic Medicine. The scientific articles
emanating from our research were all published during the years 1998 and 2000
(1-8). The publication of our results has led to a lively discussion in Sweden,
which has received large-scale attention in the media. When this book was first
edited the director general of the National Board of Forensic Medicine wrote an
official letter to the director general of the Medical Product Agency (MPA)
requesting that immediate preventive measures be taken to reduce the serious
side-effects of DXP. The problem of DXP fatalities and dependency has also
gained political interest. For example a motion was proposed to the Swedish
Parliament that attention should be paid to this issue, and the Minister of
Health and Social Affairs was asked whether it was to be dealt with or not. The
Minister of Health and Social Affairs referred the question to the MPA, who
announced in a press notification in August 2000 that the pharmaceutical
industry was being requested to supply all DXP packages with extra warning
texts in view of the lethal danger in overdosing DXP or in combining it with
alcohol. The question of restriction of DXP prescription is at present under
consideration by the Federation of Swedish County Councils and the National
Board of Health and Welfare.
An
Australian contribution
Prescription
data for Australia were compared with information on drugs taken in
self-poisoning and suicide, to determine which drugs were over-represented
(11). After adjustment for numbers of prescriptions, DXP had the fourth highest
odds ratio, after short-acting barbiturates, chloral hydrate and colchicine,
and preceding tricyclic antidepressants. It was stated that short-acting
barbiturates, chloral hydrate and DXP have little or no advantage over
corresponding alternatives, and have excessive toxicity in overdose. It was
therefore considered that they should be removed from the market.
Summary
Fatalities
due to DXP have been reported from several countries for more than three
decades. Among these reports there has been over all agreement about the
toxicity of DXP. A majority of the studies have established the high risk of
DXP poisoning and have led to the proposal that prescription of this drug
should be restricted, and sometimes even to the opinion that DXP should be
withdrawn from the market. Nevertheless, of the countries mentioned above, it
is only the two Scandinavian countries Denmark and Norway that have in fact
implemented strict regulations of prescription. In all the other countries the
problem of DXP fatalities still persists.
CHAPTER
4
Dependence
on DXP
Persons
abusing different kinds of prescription drugs may be divided into two main
categories: on the one hand the so-called ordinary people, who have narcotic
drugs prescribed because of illness and who develop a primary dependence on
these drugs, and on the other hand people already abusing other drugs, who want
to strengthen the intoxication or use the narcotic drug in the state of
withdrawal.
In the first category, of so-called therapeutic abusers, the drug is first taken in normal doses, but
later the users develop tolerance and gradually increase their doses to get the
same effect as before. Some of these abusers become physiologically dependent
and have to continue the medication to avoid withdrawal symptoms, while others
may become psychologically dependent, addicted to the euphoric or relaxing
effects of the narcotic drugs. These latter persons may develop a pattern of
increasing pathological use.
(Picture: I am
not dependent on pills! …..but I need more of them!)
According
to ICD-10 (33), a person may be diagnosed as dependent on a substance if he or
she fulfils at least three of six defined criteria during a period of twelve
months. These criteria are summarised in the following:
·
a strong craving for or a compulsion
to take the drug
·
loss of control regarding the
amount, the duration or the point in time
·
characteristic withdrawal symptoms
and/or the substance is taken to relieve or avoid withdrawal symptoms
·
marked tolerance
·
the drug occupies an increasingly
central position in life
·
continued use despite experience of
physiological as well as psychological consequences of the drug.
Although
DXP is an opioid, the possibility of addiction was thought to be low at the
time of introduction of the drug, and one early study showed that the potential
for addiction was substantially lower than that of codeine (75). Only a few
years later case reports of patients showing addiction to DXP began to be
published (76-79). First it was suggested that DXP was being used by persons already
addicted to some other drug (72), in order to potentiate the effect of the
other drug or in situations of withdrawal. Later it was shown that DXP could
also be a drug of primary abuse (80) and that dependence most frequently seemed
to develop among patients with chronic pain (81).
The
scheduling of narcotic drugs
The
narcotic conventions of the United Nations (UN) decide which drugs should be
defined as narcotic. These drugs are allowed only for medical and scientific
purposes. The reason why a substance is scheduled as narcotic is that it is
addictive. Each country that has attached itself to the narcotic conventions of
the UN may add other drugs in its own national legislation (82). The actual
narcotic conventions of the UN are founded on three international conventions:
1. The general narcotic convention of
the UN from 1961. The convention includes substances from
the vegetable kingdom that can be abused – such as cannabis, cocaine, opium,
morphine, heroin and other opiates. In June 1997 153 UN states had attached
themselves to this convention.
2. The psychotropic convention from
1971. This convention includes synthesised drugs such as LSD, amphetamine,
barbiturates, benzodiazepines and ecstasy. It is supported by 144 countries.
3. The narcotic convention from
1988. This has been accepted by 138 countries, which means that these countries
are obligated to co-operate to prevent the increasing numbers of narcotic
crimes.
In
the USA the Controlled Substances Act (C.S.A.), Title II of the comprehensive
Drug Abuse prevention and Control Act of 1970, is the legal foundation of the
government’s fight against abuse of drugs and other substances. This law is a
consolidation of numerous laws regulating the manufacture and distribution of
narcotics, stimulants, depressants, hallucinogens, anabolic steroids and
chemicals used in the illicit production of controlled substances (83).
The C.S.A. places all substances that in some manner are
regulated under the existing Federal Law into one of five schedules. This
placement is based upon the substance’s medical use, potential for abuse, its
safety and its dependence liability. The Act also provides a mechanism for a
substance to be controlled, i.e. added to a schedule; de-controlled, i.e.
removed from control; or rescheduled, i.e. transferred from one schedule to
another. The five schedules are as follows:
Schedule I. The
drug has a high potential for abuse, it has no currently accepted therapeutic
use in the United States, and there is a lack of accepted safety for use of the
drug under medical supervision. Some Schedule I substances are heroin, LSD, and
marijuana.
Schedule II. The
drug has a high potential for abuse, but it has a currently accepted
therapeutic use or currently accepted medical use with severe restrictions.
Abuse of the drug may lead to severe psychological or physical dependence.
Schedule II substances include morphine, cocaine, methadone.
Schedule III. The
drug has a potential for abuse that is lower than that of the drugs in
Schedules I and II. It has currently accepted therapeutic use. Abuse of the
drug may lead to moderate or low physical dependence or high psychological
dependence. Anabolic steroids, codeine and hydrocodone with aspirin or Tylenol,
and some barbiturates, are Schedule III substances.
Schedule IV. The
drug has a low potential for abuse relative to the drugs in Schedule III. The
drug has currently accepted medical use in treatment. Abuse of the drug may
lead to limited physical dependence or psychological dependence relative to the
drugs in Schedule III. Included in Schedule IV are Darvon, Talwin, Equanil,
Valium and Xanax.
Schedule V. The
drug has a low potential for abuse relative to the drugs in Schedule IV. The
drug has currently accepted medical use in treatment. Abuse of the drug may
lead to limited physical dependence or psychological dependence relative to the
drugs in Schedule IV. Over-the-counter cough medicines containing codeine are
classified in this schedule.
Bulk
DXP is in Schedule II, while preparations containing it (e.g. Darvon) are in
Schedule IV.
Sweden
has joined all three narcotic conventions of the UN, and therefore all the
preparations classified as narcotic drugs in these conventions are
automatically classified as such in Sweden. The National Corporation of Pharmacies
has the responsibility of placing all these substances into one of the five
schedules.
CHAPTER
5
Summary,
discussion and conclusions
The
aim of our DXP project was to test the hypothesis that the side-effects of DXP
constitute a serious public health problem in Sweden today. If the hypothesis
was verified, we anticipated that the results would provide justification for
total withdrawal of DXP from the market in the first place, or in the second
place for implementation of strict regulations in the prescribing of this drug.
Analgesic dependence among chronic
pain patients (1)
In our first study on DXP, interviews were conducted in 1992
with 265 orthopaedic patients and patients with chronic pain referred to a
rehabilitation clinic, using a structured diagnostic instrument (ADDIS/SUDDS)
in accordance with DSM-III-R (84), concerning their use of alcohol and drugs.
The interview was completed by 243 patients. Twenty-two per cent of these
patients met criteria for analgesic use disorders in accordance with DSM-III-R,
and 18.5% fulfilled DSM-IV criteria. DXP was the most common analgesic
prescribed and was used by 47% of the patients who met criteria for analgesic
use disorders. Codeine was used by 18%. Two-thirds of the patients with
analgesic use disorders did not have any other substance use disorder,
indicating that DXP might be a drug of primary dependence.
As the result confirmed earlier findings (81, 85) that
patients with chronic pain using narcotic analgesics seemed to be at
considerable risk of developing DXP dependence, it was considered that a
classification of preparations containing DXP into schedule IV would be
justified.
The combination of high toxicity and a psychoactive
effect of DXP makes it especially dangerous to individuals who have developed
dependence, since one of the most important criteria of dependence is loss of
control over the amount taken (ICD-10). Once a dependent person has
started to take a drug with dependence liability – either alcohol or other
drugs – he or she has great difficulties in discontinuing it. Many dependent
individuals have described how they have tried to control their intake, for
example by making a note every time they take a pill. In spite of this they may
wake up hours or days later and discover that they have once more lost their
control. If DXP is the drug then taken, the risk is considerable that they will
never wake up again.
The
prevalence of DXP and fatal DXP poisoning among forensic autopsies (2)
In
a second study the prevalence of DXP in the total medico-legal autopsy material
in Sweden in 1992 to 1996 was examined and characterised. (In a follow-up we
studied the total medico-legal autopsy material for the period 1997-1999).
Deceased persons with measurable levels of DXP in the peripheral blood were
included. DXP was found in blood samples from 7.5% of the total number of blood
samples. The autopsy prevalence of DXP increased by 25% during the study years.
A constantly high rate of fatal
poisonings in which DXP caused or contributed to death was found (158-227 cases
per year). The mean blood DXP concentration was 1.62 µg/g (the blood level of
DXP after a therapeutic dose is 0.05-0.75 µg/g). The cases below 50 years of
age had a significantly higher mean concentration than those above 50 years.
Autopsy cases where DXP was not found in the peripheral blood
were excluded. DXP was present in hepatic blood or cardiac blood in another 115
cases. Further, we did not investigate the main metabolite norpropoxyphene, and
thus cases where DXP could only be traced indirectly by its metabolite were
overlooked. This meant that the prevalence might have been higher than was
indicated in this study.
The high prevalence of DXP in
autopsy blood points to a high prescription rate. As mentioned above, among the
Nordic countries DXP is most frequently prescribed in Sweden. In 1996 the
prescription rate was 14.4 DDD, while the prescription rate of the second most
frequently prescribed preparation codeine was 10-11 DDD. During the years
1992-1995, 25 cases of fatal poisoning where codeine contributed to death were
reported, and only one case in which codeine was judged to be the cause of
death (74).
DXP and
alcohol (3)
Simultaneous occurrence of drugs and alcohol is often
found among self-inflicted intended poisonings. The aim of our third study was
to investigate deaths not classified as suicide, and where both DXP and alcohol
were found in the blood. Among the records for the years 1992-1996 we found 425
such cases. An increase in the number was observed, as half of the cases were
noted during the last two years of the study period.
In 42% of the cases there was a blood
alcohol concentration of less than 0.1%, in one-third this figure was more than
0.2%, and in 11% of the cases it was 0.3%. The majority of these cases were
between the ages of 30 and 59 years and 71% were male. Notes on alcoholism were
found in 16% of the cases.
In spite of warnings in the public drug
compendium and in the corresponding drug compendium for physicians against
using DXP while under the influence of alcohol or sedatives, our study showed
an increase in the simultaneous occurrence of DXP and alcohol in the blood in
autopsy cases during the five years. Our results confirmed those of earlier
studies showing that individuals who mixed these drugs did not, as one might
perhaps believe, belong to a typical street drug population, or to a group of
young people experimenting with alcohol and pills, but were middle-aged men,
habitual or social drinkers, on medication for pain. An average of 40 individuals
died accidentally every year from the dangerous combination of DXP and alcohol,
and it is therefore clear that this risk category needs to be identified by the
prescribing physicians.
(Picture: “I
suppose it won’t harm if I take another drink”)
The classification of the manner of death
in fatal DXP poisoning
(4)
In
another study we analysed the 956 cases that had been classified as fatal
poisoning during the years 1992-1996 and where DXP had caused or contributed to
death. Among these cases the manner of death was classified as accidental in 49
(5%) of the cases, suicidal in 542 cases (57%) and undetermined in 365 cases
(38%). In comparison with earlier studies (31, 36, 86) the rate of accidental
death was very low, and the number of accidents was probably under-reported.
The analysis of the death certificates and the police reports showed that cases
likely to have been accidents often were classified as undetermined.
In Sweden cases classified as undetermined are frequently
included in discussions of suicide rates (87), which in the case of DXP
poisoning may lead to an underestimation of the risk of unintentional
poisoning. An invalid classification may also lead to unnecessary suffering
among close relatives, as a suicide by a family member probably is one of the
most traumatic experiences a person can have. In many countries insurance
matters are also influenced by the classification of the manner of death.
Therefore, in order to classify a death as suicide, unambiguous evidence of
intent of the deceased to die should be established, especially in the case of
DXP poisoning, in which it is very difficult to determine whether the death was
intentional or not.
In a later study (5) we found that the classification of the
manner of death was often based on very limited grounds, and it is therefore
important to implement new routines to enlarge the base of information.
It is often questioned whether withdrawal of a toxic medical
preparation really does lead to a decrease in the number of deaths. Such
questioning is often based on the presumption that the majority of the fatal
poisonings are suicides, and that a person who really intends to commit suicide
will find other means to do so. When it comes to DXP, we do have reasons to
believe that the number of cases of accidental poisoning is considerably larger
than is officially reported.
Further, it is not the intention in all suicidal attempts
that they shall lead to death. Many people, especially youngsters, may act out
aggression or disappointment in such attempts. If the pills they grab in their
bathrooms for this purpose happen to contain DXP, the impulsive act may lead to
a tragic, unwanted death. We suggest that the number of fatal poisoning cases
would decrease considerably if DXP were withdrawn from the market.
Unmixed and combined DXP
preparations (6)
There
has been some discussion as to whether or not the combination of DXP and
paracetamol implies an increased risk. According to some investigators the risk
of death is doubled by use of Distalgesic, which contains both DXP and
paracetamol. First, DXP may cause coma, convulsions and a rapid onset of
respiratory depression and apnoea, and secondly, if the patient survives the
initial phase of respiratory depression, hepatic failure from the paracetamol
may occur a few days later (88).
We decided to examine the relation between the prescription
of various DXP preparations and their involvement in fatal poisoning in Sweden
during the years 1992-1996, to determine whether any particular kind of preparation
was over-represented. There are seven preparations containing DXP on the
Swedish market; in three of them DXP is the sole analgesic ingredient, while
four of them are combinations of analgesics. The highest ratio of prescription
rate to number of deaths, 27, was attributed to unmixed preparations. The ratio
for DXP + paracetamol-related deaths was 6.3, and for DXP + phenazone 6.4, while the
lowest ratio, 2, was found among the cases of DXP + chlorzoxazone. The unmixed
preparations, representing 26% of all DXP prescriptions during the study years,
were implicated in 62% of the DXP fatalities, a considerable
over-representation.
In spite of the doubled risk
associated with Distalgesic, we found that the unmixed preparations were
involved in considerably more deaths when the numbers of deaths were correlated
with the rates of prescription. In Sweden Distalgesic® has dominated the DXP
market ever since it was introduced in 1972 (89), although it is now losing its
share of the market, with a reduction from 58% in 1992 to 49% in 1997. On the
other hand the unmixed preparations gained in their share of the market during
the same years, from 2.5 DDD in 1990 to 4.8 DDD in 1997, an increase of 92%.
Thus we may anticipate an increase in the already high DXP fatality rate unless
restrictions are placed on the prescribing of this drug.
Age and kind of preparation in
fatal poisoning (7)
Next
to DXP, antidepressants and sedatives are the most common causes of fatal
poisoning in Sweden (56). In order to analyse the characteristics of DXP
victims in comparison with those of victims of poisonings due to
antidepressants and sedatives, a Swedish autopsy material from the six-year
period from 1992 to 1997 was examined.
The comparison showed a significant over-representation of
fatal DXP poisonings among younger people. The average ages of the deceased
varied significantly (DXP 43 years, antidepressants 51 years and sedatives 59
years). The age distribution among the
fatal DXP poisonings differed from that in Swedish sale statistics, which have
shown that the prescription rate of all compounds studied increases with
increasing age (89).
To explain the over-representation it may be speculated
whether younger people are more prone than the elderly to abuse therapeutic
drugs by reason of their euphoric effects. In order to get a kick, they might
take large doses, and in the case of DXP, with its high toxicity, the overdose
might lead to accidental death.
In comparison with other single preparations found in the
blood of the deceased, DXP was markedly predominant in causing fatal
poisonings. When the number of DXP-related deaths was considered in relation to
the prescription rate in the whole of Sweden during the years 1992-1996, the
ratio obtained was 66 (956 deaths/14.5 DDD). The ratio for the second most
frequent preparation flunitrazepam during the same years was 20. The conclusion
drawn was that DXP has a higher toxic potential than other preparations
involved in fatal poisonings.
Irrespective of its causes, the considerable
over-representation of fatal DXP poisoning should constitute a warning signal,
and preventive measures are urgently needed.
DXP in individuals suspected of
driving under influence (8)
Along
with the increasing polydrug use and abuse, increasing attention has been paid
to individuals driving under the influence of drugs, and in 1999 a new Swedish
law came into force, implying a strengthened policy regarding driving while
influenced by narcotic drugs (90).
To investigate the prevalence of analgesics containing DXP
among individuals suspected of driving under the influence of drugs, we
analysed all blood samples in which drugs were screened for in cases of
suspected driving under influence in Sweden during the years 1992-1997. DXP was
found in less than 3%, but when the number of cases was correlated to the DDD
during each year of the period, the ratio trebled from 1992 to 1997, a
significant increase. The increase in the prevalence of DXP supports the
earlier finding of an increase in the prevalence of this drug among autopsy
cases during the same period (2). In view of the high toxicity of DXP,
especially when combined with alcohol or other drugs, this trend gives reason
for concern, since the studied population represents a group of individuals who
use large doses of therapeutic or illegal drugs.
The analgesic
effect of DXP according to meta-studies
A
medical preparation with such serious side-effects as those of DXP can only be
justified if its therapeutic value widely exceeds the risks, and if no alternative
preparation of comparable therapeutic value is available. The analgesic effects
of DXP have been questioned. Comprehensive meta-studies have shown that
although it has some analgesic
effects, DXP is not superior to other available analgesics recommended for
moderate to severe pain.
In 1970 it was concluded from a review of the literature that
DXP was not superior to codeine or aspirin in terms of its analgesic effect. It
was considered that factors other than an intrinsic therapeutic value were
responsible for the commercial success of DXP, for example promotional efforts
involving high expenditure for advertising in medical journals, detailing to
physicians, and distributing free samples (91).
In a follow-up in 1977 one of the reviewing authors found that
it was doubtful that DXP hydrochloride in a dose of 65 mg provided an analgesic
effect equal to that of aspirin 650 mg. Further, he did not find any conclusive
evidence that combinations of DXP with other analgesics were more effective
than DXP or other analgesics alone (92).
Two other reviews, in 1966 and 1984, showed that DXP alone
was superior to placebo in doses of 65 mg or more, but that the effects were
questionable in doses below 65 mg. The author concluded that DXP was only
approximately 1/2-2/3 as potent as codeine. Likewise, DXP in doses of less than
65 mg was certainly no more, and possibly less effective than the generally
used doses of aspirin (93, 94).
In 1997 a systematic overview undertaken to assess the
analgesic effects of adding DXP to paracetamol (only randomised controlled
studies were included) revealed no objective evidence to support prescribing of
a combination of paracetamol and DXP in preference to paracetamol alone for
moderate pain (95).
When prescribing restrictions were implemented in Denmark in
1988, the arguments put forward against total withdrawal of DXP were that this
drug did have a therapeutic value in some patients and that no satisfactory
alternatives for patients with moderate pain were available. The meta-studies contradict
these arguments, and today, more than ten years later, there are alternative
analgesic preparations designed for the same patient category, but which lack
the high toxicity of DXP and thereby are considerably less dangerous. Examples
are the anti-inflammatory preparations with a prolonged effect, such as
ibuprofen, which have been reported to be more effective than DXP (96-98).
Another alternative is tramadol, an opioid with a lower addiction liability
than DXP and without DXP’s high toxicity (99, 100). Tramadol has only recently
been introduced onto the Swedish market, but in Germany, for example, it has
been on the market for more than three decades.
Summary
The
findings in our investigation have shown a clear and distinct pattern. DXP
causes the largest number of fatal poisonings in Sweden today, not only in
absolute figures, but also when the number is correlated with the prescription
rate. Unmixed preparations, i. e. those containing only DXP, are involved in
considerably more deaths than the combined preparations, when the number of
fatal poisonings is considered in relation to the rate of prescription.
Individuals below the age of 50 years are over-represented
among cases of fatal poisoning where DXP has caused or contributed to death,
and middle-aged men seem to be most prone to mix alcohol and DXP without any
intent to commit suicide. Further, individuals abusing drugs are at
considerable risk of dying accidentally from ingestion of DXP, just like
younger people experimenting with alcohol and pills or acting out aggression or
disappointment.
The number of accidental DXP poisonings are under-reported,
and unintended fatal poisonings are often hidden not only among the deaths
classified as undetermined, but also among those interpreted as suicides.
Patients on DXP medication for pain run a considerable risk
of becoming dependent on their medicine, even within the prescribed doses.
There has been a significant increase in the prevalence of
DXP among autopsy cases and among individuals suspected of driving under the
influence of drugs or alcohol.
Finally, we agree with the request made by several clinical
researchers before us that DXP should be withdrawn from the market today and
replaced by analgesics with less serious side-effects. This would save a
considerable number of human lives each year.
APPENDIX 1
Eight studies on dextropropoxyphene
In the following we present the papers on which this
book is based. The original articles are recommended for those who whish to
have more details. Permission to carry out all studies was received from the
Ethical Committee of Uppsala University. The persons working in the project
have been under obligation to preserve confidentiality. All information about
patients has been stored in accordance with current security regulations and
consideration has been paid to the privacy of the deceased and of his or her
surviving relatives and friends.
I. Analgesic use disorders among orthopedic
and chronic pain patients at a rehabilitation clinic.
Substance Use & Misuse 1998;
33:1375-1385.
The main purpose of study I was to document the prevalence of past
and present analgesic use disorders, including those with drugs containing DXP
or codeine, among orthopaedic patients and patients with chronic pain treated at
a Swedish rehabilitation clinic in 1992. The patients were referred by the
Swedish National Health Insurance or by private doctors for further evaluation.
Myalgia, myositis and unspecified muscular pain, disc degeneration and changes
in the cervical spine were the most common diagnoses on referral.
To assess the occurrence of substance use disorders among
these patients, they were all interviewed concerning their consumption of
alcohol and drugs. The interview was introduced as part of the admission procedure
and designed to elicit information permitting a diagnosis of substance use
disorders in accordance with the DSM-III-R criteria (85). The DSM-III-R
diagnosis was classified into dependence and
abuse.
To evaluate the attitudes of the
staff members towards the new routine, a structured interview with these
members was conducted. The attitudes of the patients were evaluated by means of
a questionnaire sent to them after discharge.
Results
The interview was completed by 243 patients. Of these, 54 patients (22%) were found to show
dependence or abuse of analgesics according to DSM-III-R. DXP was the preparation most often prescribed and was used by 47%
of the patients fulfilling the criteria for dependence or abuse. The difference
between the group with no analgesic use disorder and the group meeting the
DSM-III-R criteria for such a disorder was significant (p=0.003) regarding DXP
(Table 1).
Table 1. The prevalence of use of different analgesic
preparations by the total group, by patients with no analgesic use disorders
and by patients with analgesic use disorders.
Total No analgesic Analgesic
group disorder use disorder
(n=243) (n=189) (n=54)
DXP 32% 26% 47%*
Codeine 12% 9% 18%
Paracetamol 30% 30% 30%
ASA 5% 5% 5%
ASA=acetylsalicylic acid *p=0.0003
Patients who were dependent on analgesics and/or sedatives
were helped to reduce their use of drugs during their stay at the hospital.
They were offered alternative pain relievers, physical training, heat baths and
medical information. In the cases where the gradual reduction was not
completed, this was continued by the patient’s own general practitioner. Three
patients who had developed dependence on alcohol were referred directly to the
treatment centre.
Discussion
and conclusion
Our results confirm the suggestion of earlier studies (81, 85) that
patients with chronic pain are at risk of developing dependence on DXP when
using it for pain relief. Two-thirds of the patients with analgesic use
disorders did not have any other substance use disorder, indicating that the
risk of developing an analgesic dependence syndrome among chronic pain patients
is not linked to other kinds of drug problems. This finding also supports
earlier results (80). Thus periodic assessment of patients using narcotic
analgesic drugs is important, even when they follow the prescribed doses. The evaluation of the attitudes of the staff
members and patients towards the new routine showed that both staff and
patients were overwhelmingly positive to the interview routine, and the use of
a structured interview for documenting drug use among patients with chronic
pain can therefore be recommended.
Forensic Medicine research
II.
The prevalence of dextropropoxyphene in
autopsy blood samples .
Forensic
Science International 1998; 96:135-142
The
aim of this study was to determine the current prevalence of DXP in the total
forensic material in Sweden during the five-year period from 1992 to 1996, in
relation to age and blood concentration of DXP.
The
analysis was made on 23,691 blood samples sent by the six forensic institutes
to the national laboratory in 1992-1996. The blood samples were analysed for
DXP. All cases with a measurable amount of DXP in peripheral blood were
included in the study. Simultaneous findings of paracetamol and alcohol were
considered in the analyses. Death certificates were analysed in all cases
concerning the cause and manner of death.
Results
DXP
was found in blood samples from 1,782 (7.5%) of the 23,691 blood samples. The
DXP prevalence increased significantly by 25% from 1992 to 1996. The mean blood
DXP concentration was 1.62 µg/g (the DXP level in the blood corresponding to
therapeutic doses ranges from 0.05-0.75 µg/g). Of the 1,782 cases 60% were men
and 40% were women. The mean age was 54 years (range 15 to 96). A significantly
higher DXP level (2.36 µg/g) was found in the group aged < 50 years compared
with the cases > 50 years of age (1.04 µg/g).
As seen in Table 2, cases with a blood DXP level of >
0.75 µg/g were distributed fairly equally between the years 1992, 1993, 1994
and 1995 (n = 139, 162, 154 and 163 respectively), but there was an increase to
217 cases in 1996.
Table 2. The number of blood
samples, the prevalence of DXP in peripheral blood and
the number of cases with a
blood DXP concentration < and >
0.75 µg/g in each year between 1992 and 1996.
Blood DXP DXP < 0.75 > 0.75
samples in blood prevalence µg/g µg/g
n n %
1992* 4,511 308 6.8 169 139
1993 4,581 330 7.2 168 162
1994 4,714 359 7.6 205 154
1995 4,953 364 7.3 201 163
1996 4,932 421 8.5 204 217
total 23,691 1,782 7.5 947 835
Paracetamol
was found in 53% of the 1,782 cases (mean 75 µg/g; therapeutic level 2.5-25
µg/g). The cases < 50 years of age had a significantly higher level of
paracetamol than those aged > 50 years. A significantly higher level
of paracetamol was also found in the group with a blood DXP level >
0.75 µg/g compared with the group with blood DXP < 0.75 µg/g.
Alcohol was found in the blood in 43% of the 1,782 cases
(mean blood alcohol concentration 0.14%). A significantly higher percentage of
the cases < 50 years of age than of those aged > 50 years had
alcohol in the blood, and this was also true in the group with blood DXP > 0.75 µg/g compared with < 0.75 µg/g.
Fifty-four per cent (956) of the 1,782 cases died of fatal
poisoning, and in 707 (74%) of these the blood DXP level was > 0.75
µg/g.
Discussion and
conclusion
The
prevalence of DXP in autopsy cases in our study increased by 25% from 1992 to
1996 and the study confirmed the constant rate of 112-160 cases per year of
fatal poisoning with DXP in Sweden since the early 1970s (72). The mean death
rate among the fatal poisonings with a blood DXP concentration > 0.75
µg/g in this study was 141 cases per year. The follow up during the years
1997-1999 showed that the prevalence increased significantly by 35% from 1992
to 1997 (9.2%) and that the number of fatal DXP poisonings remained high during
the years 1997, 1998 and 1999 (224, 195 and 217 respectively).
A striking finding was the significantly higher levels of
both DXP and paracetamol in cases < 50 years of age. This together with the
significantly higher prevalence of alcohol in the blood in cases with DXP may
confirm some alarming reports about young people using analgesics to potentiate
the effects of alcohol (101). The high availability of DXP preparations makes
it a drug of great interest to adolescents (102). The constantly high rate of
fatal DXP poisonings cannot be expected to decrease unless preventive measures
are taken. Other Scandinavian countries, such as Norway and Denmark, have
managed to decrease the rate of fatal DXP poisonings through government
regulations for prescription. As the defined daily dose of DXP preparations in
Sweden is six times as high as in Denmark and nine times as high as in Norway
(Table 3), the introduction of similar regulations in Sweden should be
considered.
Table 3. Sales of
dextropropoxyphene in different Scandinavian countries. DDD = defined daily
dose/1000 inhabitants during a 12 - month period.
1990 1994 1996 mean
DDD DDD DDD DDD
Sweden 13.9 14.7 14.4 14.5
Norway 1.6 1.6 1.6 1.6
Denmark* NA 2.7
2.0 2.4
*) use in hospital not
included. NA = not available
III.
Middle-aged men – a risk category
regarding fatal poisoning due to dextropropoxyphene and alcohol in combination.
Preventive
Medicine 2000; 31:103-6
The aim of
study III was to determine the characteristics of non-suicidal deceased persons
with both alcohol and DXP in the blood, among the total medico-legal autopsy
material in Sweden during the years 1992 to 1996. The requirements for
inclusion in the study were that DXP was present in peripheral blood, that a
blood alcohol concentration > 0.01% was found, and that death was not
classified as suicide.
Results
As
mentioned above (study II), in the study above DXP was found in the blood in
1,782 cases, and in 766 of these the death was classified as suicide. These 766
cases were therefore excluded from study III. Alcohol was noted in 425 of the
remaining cases. Almost half of the 425 cases (47%) with both alcohol and DXP
in the peripheral blood were found in the two last years (1995-1996). The
majority of the cases were 30–59 years old and 71% were male (Fig. 1). The mean
blood alcohol concentration was 0.14%. Notes on alcoholism were found in 16% of
the cases and drug addiction in 8%.
Figure 1. The age distribution of males and females with both DXP
and alcohol in the blood.
n = 425
The
cause of death was classified as fatal poisoning, with DXP causing or
contributing to death, in 220 (52%) of the deceased. The manner of death among
these 220 cases was accidental in 26 cases (12%) and undetermined in 194 (88%).
Among the 205 (48%) cases not classified as fatal poisoning the causes of death
were distributed as follows: 83 (19.5%) natural, 25 (6%) chronic alcoholism,
and 97 (22.5%) other injuries.
Discussion and
conclusion
As many as 42%
of the analysed cases had a blood alcohol concentration of < 0.1% (29% <
0.05%), and of these 12.5% were classified as alcoholics and 10% as drug
addicts. Thus the majority of these 42% were “normal” drinkers, without a
developed alcohol tolerance. We hypothesise that such persons mix DXP and
alcohol when they are in pain, a possibility which might be supported by the 83
cases classified as natural deaths, or when they are in situations where it is
common to use alcohol.
The fact that the majority (71%) of the fatal poisoning cases
were between 30 and 59 years old indicates that death from the effects of a
combination of DXP and alcohol does not typically occur among young people, but
rather among middle-aged men (71% were male).
The alcohol consumption in Sweden is among the lowest in the
European Union (EU). The general drinking pattern, however, which is
characterised by occasional heavy consumption (compared with the pattern in
many other countries where frequent but low consumption is more common),
constitutes a high risk when it comes to fatal poisoning caused by combination
of alcohol and other drugs.
In the public drug information compendium (FASS), the
presentation of DXP preparations includes a warning against using the drug
while under the influence of alcohol or sedatives. In the corresponding drug
compendium for physicians, the information on all DXP preparations includes a
warning against prescribing the drug to alcoholics or drug addicts. The
increasing proportion of cases with both alcohol and DXP in the blood, during
the years of our study shows that warnings to patients and recommendations to
physicians are not sufficient to lead to any decrease in death rates due to
simultaneous poisoning with alcohol and DXP.
In the absence of strict regulations by the authorities
concerning prescription of DXP, it should be the responsibility of the
physicians before prescribing this drug to ask the patient whether he or she
uses alcohol, to describe the life-threatening risks of simultaneous intake of
alcohol and to actually ask the patient if he or she is willing to abstain from
alcohol during the treatment with DXP. If the patient seems to be unsure or
negative about being abstinent, the physician should consider a less hazardous
analgesic.
IV.
The manner of death among fatalities
where dextropropoxyphene caused or contributed
to death
Forensic Science
International 1998; 96:181-187
The
aim of study IV was to investigate the manner of death among fatalities where
DXP caused or contributed to death (= DXP fatality) in Sweden during the
five-year period from 1992 to 1996. As mentioned above (study II), the
certifying physicians classified 956 cases as DXP fatalities. The autopsies
were performed by a total of 40 physicians.
Results
Figure
2 shows the distribution by age of the 956 autopsy cases classified as DXP
fatalities. Most cases, 229 (24%), were found in the age-group 40-49 years.
Figure
2. Histogram showing the number of fatalities due to DXP in the different
age-groups. n = 956
The
mean age of the 956 fatal DXP poisoning cases was 47 years (range 15-96) and
56% were men and 44% women. The mean DXP concentration in the blood in the DXP
fatalities was 2.60 µg/g.
Among the 956 DXP fatalities, the manner of death was
recorded as accidental in 49 cases (5%), suicidal in 542 (57%) and undetermined
in 365 (38%). Table 4 presents the mean frequency and range of the three
manners of death in the different forensic medicine districts during the study
years (Fig. 3). The rate of accidental death differed significantly between
district C and districts E and F. District B had a significantly higher rate of
suicide than all the other districts apart from D, while district E had a
significantly lower rate than all the others.
Table 4. The mean frequencies and ranges of the different manners of
death among fatalities due to DXP, in the six forensic medicine districts A-F,
during the study years 1992 – 1996 (%).
District Accident
Range Suicide Range Undetermined Range
%
% % % % %
A 6 0
– 10 54 37 -75 40 17 – 53
B 5 0
- 11 73 59 - 88 22 8 – 30
C 9 2
- 17 60 55 - 67 31 16 - 48
D 6 0
- 11 62 48 - 79 32 12 – 52
E 1 0
- 3 33 12 - 50 66 47 - 88
F 1 0
- 3 55 41 - 63 44 37 - 56
Mean 5 3 - 9
57 53 - 60 38 34 - 44
Among
the 25 physicians with ten or more autopsies, the accident classification rate
varied from 0% to 17%, the suicide classification rate from 25 to 83% and the
rate of undetermined manner of death from 8% to 71%.
Discussion and conclusion
In
our study the percentage number of deaths classified as accidental was very
low, a result quite different from that of earlier studies (31, 85), and we
suggested that accidents were probably under-reported. We discovered a number
of deaths among those classified as undetermined that might have been
classified as accidental if the physicians had had access to more information.
Figure 3. The six forensic medicine districts
Our
study supports some alarming reports that have shown that some young people use
analgesics to potentiate the effects of alcohol (101, 102). In our study as
many as 64% of the fatal poisoning cases of ages 15-29 years had alcohol in the
blood. In 5% of the cases the manner of death was classified as accidental, in
59% as suicidal and in 36% as undetermined. We suggest that rate of accidental
death among these young people was probably underestimated and that many of
these young men and women died without any intention to do so.
In Sweden the alternative to a report of suicide on death
certificates in fatal poisoning cases has become an undetermined manner of
death, thus reducing judgements of deaths as being accidental to a minimum.
Further, under-reporting of accidents will increase the risk that knowledge of
the high toxicity will not reach the population consuming this drug, nor will
it reach the physicians, the producers or the responsible authorities.
Although the rates of the different manners of death were
fairly stable during the study years in all Sweden, our investigation showed
that the classification criteria seemed to vary between the Swedish forensic
medicine districts and between the individual physicians.
Since valid death statistics concerning the manner of death
in DXP fatalities are needed to provide a basis for preventive measures,
special attention should be paid to the classification process, in order to
increase the uniformity of the assessments among the different physicians, and
also to avoid under-reporting of accidental cases.
V. Suicides may be over-reported and
accidents under-reported
among fatalities due to dextropropoxyphene.
Journal of Forensic Sciences 1999;
44:334-338
In order to
analyse the basis of the process leading to classification of the manner of
death in DXP fatalities, a set of operational criteria (103) was applied retrospectively
to an autopsy material at one of the six departments of forensic medicine in
Sweden (Uppsala) examined during the six-year period from 1992 to 1997.
These criteria were divided into explicit and implicit
expressions of the deceased person’s intent to die. Unambiguous verbal and
written statements made by the deceased showing his or her intent to die were
regarded as explicit criteria, while statements from relatives, acquaintances
and others formed the basis of the implicit criteria. Implicit evidence of the
deceased person’s intention to die was condensed into 11 criteria, for example
expressions of hopelessness, a previous history of suicide attempts or suicide
threats, a history of stressful events or a significant loss, and a history of serious
depression or a mental disorder.
Results
During the
six-year period 1992-1997, a total of 4,306 autopsies were performed at the
forensic medicine department. Among these deaths, 113 (2.6%) were classified as
fatal DXP poisoning. Suicide was recorded in 84 (74%) of the 113 DXP fatalities
and an undetermined manner of death in 24 (21%). In three of the cases the
death was judged to be accidental. Overdose of DXP was reported to be a
contributory cause of death in two cases, where chronic alcoholism was judged
to be the primary cause.
Explicit expressions of the deceased’s intent to die were
documented in 29 (26%) of the 109 analysed cases (In four cases no analysis
could be performed). In 46 cases only implicit and no explicit criteria were
found. The total number of implicit criteria in individual cases never exceeded
three and in 34 cases no criteria of any type were documented.
The mean blood DXP concentration in the 109 cases where
toxicological analyses were available was 3.33 µg/g. The mean blood DXP
concentration was significantly higher (95% confidence interval) among the
suicide cases (3.74 µg/g) than among those classified as undetermined (1.90
µg/g).
Discussion
and conclusion
The
classification of the manner of death in DXP fatalities was often based on very
limited grounds. Information from relatives, friends and others concerning the
deceased person was rarely available. The shortage of information probably led
to deficiencies in the death statistics concerning DXP fatalities.
Considerable under-reporting of accidents and probable
over-reporting of suicides were found. In the 34 cases where no criteria of any
type were documented, 15 cases were classified as suicide and 14 as
undetermined, showing that suicide was chosen as often as undetermined as the
manner of death even when no suicidal criteria supported the classification.
A high blood DXP concentration per se seemed to be a
criterion of suicidal intent. When it comes to addicts it is difficult to
interpret drug concentrations, since development of tolerance and loss of
control of the amount taken are important criteria of substance dependence
(ICD-10). These dependence syndrome behaviours might lead to accidental
fatalities, especially when DXP is the consumed drug.
A case where a DXP fatality in a drug addict was classified
as suicide is presented to illustrate the difficulty in interpreting the blood
DXP concentration.
A man aged 39 died of poisoning. A blood alcohol
concentration of 0.05% and a blood DXP concentration of 4.5 µg/g were found.
According to hospital records he was a known alcoholic and abuser of
therapeutic drugs, and treatment with the anti-alcoholic agent disulfiram had
been withdrawn within the last two weeks. The man died in the apartment of his
wife’s grandmother. He had gone there to use her telephone. He made some
telephone calls, and suddenly the grandmother heard a sound, and found him
lying on the floor, without any signs of life. On arrival of the emergency team
he was dead.
The
death was classified as suicide. This could instead be an example of an
accidental death caused by a combination of DXP and alcohol. Since he was an
abuser of therapeutic drugs, his tolerance of DXP was probably increased, but
when the disulfiram was withdrawn and he started to drink alcohol again, the
combination became lethal.
In order to guarantee valid death statistics, the amount of
information constituting the basis of the certifying process has to be
enlarged. This would require implementation of new routines, including interviews
of relatives, acquaintances and significant others, for example psychiatrists,
to obtain the information required to assess the deceased’s intention to die.
This is especially important when DXP is the consumed drug.
A set of operational criteria would facilitate the difficult
certifying process, and the authors recommend use of the set of explicit and
implicit criteria applied in this study.
VI. Correlation
between prescription of various Dextropropoxyphene
preparations and their involvement in fatal poisonings.
Forensic Science International 1999;
103:125-132.
The
aim of this study was to examine the relation between the prescription of
various DXP preparations and their involvement in fatal poisoning in Sweden
during the years 1992-1996, to determine whether any particular kind of
preparation is over-represented.
DXP is the sole analgesic ingredient in Dexofen (Astra) and
Doloxene (Eli Lilly), each containing 50/100 mg DXP, and in Dolotard (Nycomed),
containing 150 mg DXP. As Dolotard represented only 4% of the sales of unmixed
preparations during the study years, this category consisted mainly of Dexofen
and Doloxene.
The four combined preparations are Doleron (Astra),
containing 100 mg DXP, 350 mg acetylsalicylic acid (ASA) and 150 mg phenazone; Paraflex
Comp (Astra), containing 45 mg DXP, 500 mg ASA and 125 mg chlorzoxazone; and
Distalgesic (Eli Lilly) and Dexodon (Tika), containing 32.5 mg DXP and 325 mg
paracetamol. Prescriptions of Dexodon (not introduced onto the Swedish market
until 1995) constituted less than 4% of all prescriptions of DXP + paracetamol
combinations in 1996.
Specifications of the therapeutic substances primarily
responsible for the poisoning are not always stated on the death certificate,
which is the reason why all fatal poisoning cases where DXP was present in
peripheral blood were included in the study. Since alcohol and other drugs can
potentiate the effects of DXP so that it becomes fatal even in doses within the
therapeutic limits, cases with DXP levels below the upper therapeutic limit
(0.75 µg/g) were also included.
The assessment of which DXP preparation the deceased had
consumed was based on toxicological analyses. When no other analgesic compound
was found besides DXP in the peripheral blood, we concluded that the consumed
drug was DXP alone.
It was found to be a complicated question to decide whether
paracetamol in the blood indicated intake of a compound consisting of DXP +
paracetamol, or whether it meant that the deceased had consumed an unmixed DXP
preparation together with some other preparation containing paracetamol. We
therefore calculated the ratios between paracetamol and DXP in the blood in 30
cases where, according to the death certificate, a compound containing both DXP
and paracetamol was the consumed drug. The mean ratio of paracetamol/DXP in
these samples was 80 (range 35-183).
A compound consisting of DXP + paracetamol was believed to
have been used when the paracetamol/DXP ratio in the peripheral blood was in
the range 35-185. With ratios < 20 the consumed drug was considered to have
been an unmixed preparation. Cases in the range 20-35 and > 185 were not
categorised, since they could have belonged to either of the two categories.
Results
The
study comprised 834 cases. As shown in Table 5, the highest mean ratio of
DXP-related deaths/DDD, 27, was found among the unmixed preparations. The death
ratio attributed to DXP + paracetamol was 6.3 and that to DXP + phenazone, 6.4,
while the lowest ratio, 2, was related to DXP + chlorzoxazone. The death ratio
of each of the preparations seemed to be fairly constant during the study years
(Table 5).
Table
5. Distribution of fatal poisonings ascribed to DXP alone, DXP + paracetamol,
DXP + phenazone and DXP + chlorzoxazone during the years 1992-96, the prescription
rate in defined daily doses (DDD), the number of fatal poisoning per DDD
(n/DDD), and the mean ratios of each preparation during the 5-year period
Year Total DXP alone DXP +
paracetamol DXP +
phenazone DXP + chlorzoxazone
n DDD
n/DDD n DDD
n/DDD n DDD
n/DDD n DDD
n/DDD
1992 132 80 3.2 25 38
8.8 4.3 10 1.4 7.1 4 1.7 2.3
1993 177 92 3.3 27.8 72
8.5 8.5 10 1.4 7.1 3 1.5 2.3
1994 155 91 3.8 24 56
8.4 6.6 4 1.0 4.0 4 1.4 2.9
1995 170 118 4.2
28 44
8.5 5 6 0.9 6.7 2 1.3 1.5
1996 200 136 4.6
29.5 57
8.0 7 5 0.7 7.1 2 1.3
1.5
Mean
834 517 3.8
27 267
8.4 6.3 35 1.1 6.4 15 1.4 2.0
Discussion and
conclusions
The
unmixed DXP preparations were considerably over-represented among the fatal
poisonings when related to the prescription rate. If all the excluded cases
with ratios between 20 and 35 and >185 had been included in the DXP +
paracetamol category, the death ratio would have been 8.7, which would still be
one-third of the ratio of unmixed preparations. Any other distribution of the
98 cases would lead to an increase in the death ratio attributable to
preparations containing DXP alone. Thus the main finding in our study would not
be invalidated by the inclusion of these cases.
Unmixed preparations, with their higher content of DXP, may
be more attractive to many consumers because of their narcotic (euphoric)
effects rather than by reason of any analgesic superiority. Another possibility
is that unmixed preparations may erroneously have been considered safer than
combinations of DXP and paracetamol, as reports of poisonings have been most
frequently concerned compounds containing both drugs, probably because of the
predominance of these mixed compounds on the market. In Sweden Distalgesic has
dominated the DXP market ever since it was introduced in 1972, although it is
now losing ground. On the other hand the market share of the unmixed
preparations is increasing, and has doubled from 1990 to 1997, a fact which
could probably lead to an even higher rate of fatal DXP poisoning.
VII. Among fatal
poisonings dextropropoxyphene predominates in younger people, antidepressants
in the middle-aged and sedatives in the elderly.
Journal of Forensic Science 2000; 45:7-10.
Next
to DXP, antidepressants and sedatives are the most common causes of fatal
poisoning in Sweden (73). In order to analyse the characteristics of DXP
victims in comparison with those of victims of poisonings due to
antidepressants and sedatives, a Swedish autopsy material from the six-year
period 1992 to 1997 was examined. Cases
where DXP, antidepressants or sedatives contributed to death in combination
with each other or with other drugs were excluded.
Results
During
1992-1997, a total of 4,306 autopsies were performed at the forensic medicine
department under study. In 202 cases DXP, antidepressants or sedatives caused
death. Among these, DXP caused death in 78 cases (39%), antidepressants in 49
cases (24%) and sedatives in 75 cases (37%). The figure for DXP may be compared
with the 30 cases (15%) caused by the second most common compound found,
flunitrazepam.
The victims of poisoning by DXP, antidepressants or sedatives
shared a similar history of alcohol/drug abuse (20%), depression (31%) and
somatic illness (25%). They were mostly living alone at the time of death (>
60%), the majority died at home (81%), and suicide was the most frequent manner
of death (73%).
The mean age of the cases of DXP fatalities (43 years,
confidence interval [CI] 39-47) was significantly lower than that of the cases
of fatal poisoning due to antidepressants (51 years, CI 48-54) and sedatives
(59 years, CI 55-63), and the mean age of the sedative poisoning cases was
significantly higher than that of the other two drug categories.
The age differences between the three types of drug poisoning
are illustrated in Figure 4. There was a predominance of DXP in the three
younger age groups (75% of all cases), a fairly equal distribution of the three
drugs in the age group 40-49 years and a predominance of antidepressants and
sedatives in the age group 50 to 59 years. In the older age groups, above 59
years, the majority of the poisonings were due to sedatives (77% of all cases).
Figure
4. The distribution of fatal poisoning by age group and type of drug. n = 202
Discussion and
conclusions
Age
seemed to be an important characteristic when it came to the choice of drug.
The mean age of the DXP cases was significantly lower, and that of the sedative
cases significantly higher than the mean ages of the other two drug groups.
Swedish sales statistics have shown that the prescription rate of all the
compounds studied increases with increasing age (89). Table 6 shows the
distribution of the prescription rates of DXP, antidepressants and benzodiazepines
by age in 1996 in the studied area.
Table 6. The prescription rates of DXP, antidepressants and
benzodiazepines, in DDD, in 1996 in the studied area.
Age-group, yrs DXP Antidepressants Benzodiazepines
20 - 29 2.0 12.7
4.1
40 - 49 9.2 44.0 30.
70 - 79 41.7 58.0 97.0
The
predominance of sedatives as cause of death among the elderly in cases of fatal
poisoning might be explained by a very high prescription rate of such drugs at
older ages, but the prescription rate of DXP could not explain the predominance
of DXP fatalities among younger people. It might rather have been expected that
the antidepressants, which were mostly prescribed among younger people, would
have been predominant in the younger group.
An analysis of the occurrence of mental disorders in relation
to age revealed no differences that could explain the differences in drug
choice. Somatic diseases were found in significantly more cases among the
elderly, giving no explanation for why DXP was used more by younger persons.
One reason for the over-representation of younger people
among the DXP victims could be that they are more prone than the elderly to
abuse therapeutic drugs by reason of their euphoric effects. In order to get
the kick, they might take large doses, and in the case of DXP, with its high
toxicity, the overdose might lead to accidental death. Sedatives are not as
toxic as DXP, and victims of accidental overdose of sedatives are thus more
often rescued. Since antidepressants lack direct euphoric effects, they are not
abused to the same extent as DXP and sedatives, which may explain the
predominance of DXP in fatal poisonings among younger people in spite of the
higher prescription rate of antidepressants.
VIII.
The prevalence of analgesics containing
dextropropoxyphene or codeine in individuals suspected of driving under the
influence of drugs
Forensic
Science International 2000; 112:163-169
The aim of
study VIII was to investigate the prevalence of analgesics containing DXP or
codeine in the blood among individuals suspected of driving under the influence
of drugs during the years 1992-1997.
Results
During
the years 1992-1997, drugs were screened for in 4,896 cases. DXP was found in
130 (2.7%) and codeine in 388 (7.9%) of these blood samples In 32 cases both
drugs were found.
Table 7 gives the number of cases involving each preparation in
relation to the DDD during each year of the period 1992-1997. The mean ratios
for DXP and codeine for this six-year period were 1.6 and 5.9 respectively. The
DXP ratio trebled from 0.99 in 1992 to 2.89 in 1997, while the codeine ratio
showed a slight decrease, by 9% (Table 7).
Table 7. Distribution of cases with DXP and codeine during the years
1992-1997. The prescription rates of the respective drugs, presented as defined
daily dose per 1000 inhabitants and year (DDD), and the number of cases per DDD
(N/DDD), are given. The mean ratios for DXP and codeine during the 6-year
period are also given.
.
DXP DDD/ N/DDD Codeine DDD/ N/DDD
N 1000 inh. (DXP) N 1000 inh. (codeine)
.
1992 16 16.3 0.99 61 10.1 6.04
1993 15 12.8 1.17 52 10.4 6.04
1994 18 13.9 1.30 85 11.3 7.52
1995 19 13.8 1.37 66 11.6 5.69
1996 27 13.7 1.97 64 11.3 5.67
1997 35 12.1 2.89 60 10.9 5.50
.
mean 1.62 5.90
.
Other
drugs were found to the same extent among the DXP and codeine cases and
benzodiazepines were present in as many as 346 (71%) of the 486 cases.
Amphetamine and/or cannabis was found in 184 cases (38%).
Discussion and
conclusions
The
prevalence of DXP (< 5%) and of codeine (< 9%) among individuals
suspected of driving under the influence of drugs was rather low during the
study years, and it is concluded that analgesics containing DXP or codeine are
not drugs of primary interest in this specific population.
Although the mean ratio of codeine cases to DDD was almost
four times that of DXP during this period, the DXP/DDD ratio trebled, while the
codeine ratio seemed fairly constant, with a slight decrease (9%) between 1992
and 1997. The significant increase in the prevalence of DXP supports the
earlier finding of an increase in the prevalence of this drug among autopsy
cases during the same period (2). In view of the high toxicity of DXP,
especially when combined with alcohol or other drugs, this trend gives reason
for much concern, since the studied population represents a group of
individuals who use large doses of therapeutic or illegal drugs.
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Correlation between prescription of various dextropropoxyphene preparations and
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Fatalities
due to use or misuse
of pain-killers
This report is based on the
research concerning the analgesic preparation dextropropoxyphene undertaken by
Birgitta Jonasson, Dr Med. Sci., and Ulf Jonasson, graduate student in Public
Health in Sweden. Their research, based on forensic medicine data, has led to
eight scientific papers, all published in international scientific journals,
and one doctoral thesis. A second thesis will be presented in March 2001.
Early
in the project they found a considerably high rate of fatal poisonings due to
DXP, both suicidal and accidental. They then became aware of the fact that if
human lives were to be saved, it would be necessary to inform the society
outside the academic world of the results of the research.
The National Board of Forensic Medicine
agree about the importance of disseminating their results and has edited this
report, which is intended among others, for general practitioners, journalists,
politicians and the general public. The Swedish version of the report has
attracted much attention and so far has been printed three times.
Since there is reason to believe that the
problem of constantly high rates of DXP fatalities is not limited to Sweden,
the authors and the National Board of Forensic Medicine share the hope that the
translation of this report into English will constitute a useful contribution
to the debate in other countries
