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GENERATION AND USE OF POST-MORTEM TOXICOLOGY DATA
EAPCCT International Congress
Athens, 2 May 2007
Erkki Vuori, professor
Department of Forensic Medicine
University of Helsinki
FORENSIC TOXICOLOGY
”The study and practice of the application of
toxicology to the purposes of law”
The task is to produce valid toxicological information
for the administration of justice and to improve the
legal protection of individuals and society.
As to the analysis of human samples, there are two
key questions: Has the person under investigation been exposed
foreign substances
Has s/he been under the influence of alcohol, drugs or
other xenobiotics.
FORENSIC TOXICOLOGY 2
Investigation of living persons Driving under the influence of alcohol or drugs Clinical forensic toxicology
- Victims and offenders of assault- Drug-facilitated crime- Drug-running- Child welfare- Drunkenness in the workplace
Drug testing programs- Workplace- Schools- Armed forces- Correctional facilities- Treatment of drug-dependent persons
Post-mortem toxicology
POST-MORTEM TOXICOLOGY
Analytical results of a post-mortem investigation are
utilized to determine the cause and manner of death. Poisoning can be the:
Underlying cause of death (WHO Ic ”initiated the train of morbid events leading directly to death”)
Immediate cause of death (WHO Ia ”condition with the symptoms of which the deceased died”)
Contributing cause of death (WHO II)
Traditionally, the results of a single forensic case are
used for the sake of the deceased in question only. Over time, cases accumulate to form a greater whole,
which can provide information that goes far beyond
the original purpose of the routine casework.
EPIDEMIOLOGICAL STUDIES, REQUIREMENTS
The results should be derived annually from a known
population or area. The analytical practices of the laboratory should be
known and should remain stable over years. Scope and sensitivity of drug screening (“cut offs”) Interpretation of the analytical results If several laboratories are involved in an area the
detection limits and analytical principles should be compatible and known
The laboratory should have an information
management system In prospective studies, the questions to be studied
can be set out beforehand, while in retrospective
studies they must fit with the existing data.
FINLAND YEAR 2004, STATISTICS
Inhabitants 5.23 millions
Number of deaths 47,757
Number of forensic autopsies 11,371 (23.8%)
Number of clinical autopsies 3,952 (8.3%)
Number of toxicogical analyses 6,109 (12.8%)
FINLAND IS AN IDEAL COUNTRY FOR POST-MORTEM TOXICOLOGICAL INVESTIGATIONS
High autopsy rate Extensive use of post-mortem toxicological services All post-mortem toxicology is centralized to one
laboratory by law The screening methods are comprehensive and have
been accredited since 1997 The laboratory gets as feedback a copy of the death
certificate from all cases investigated The laboratory has an information management
system with demographic data The National Agency for Medicines publishes
statistics annually on the consumption of medicines
TYPICAL FEATURES OF FATAL DRUG POISONINGS
Frequently several drugs are present
Frequently alcohol has been taken simultaneously
Frequently the victim has committed suicide
Drugs of abuse are common
Victims include young people also
THE MOST IMPORTANT FINDING
A combination of several drugs is typically found in the same subject.
If all findings are included in the classification, the number of possible fatal combinations is too high.
The forensic pathologist always has a possibility to choose the most important finding.
If not stated, the drug which has the greatest ratio of found concentration in relation to its therapeutic concentration is taken as the basis of the classification
The method used is a crude mathematical procedure However, this yields reasonable results from year to
year and a similar ranking of the most dangerous drugs
THE ATC CLASSIFICATION SYSTEM
Classifies drugs according to anatomical, therapeutic and chemical properties
Gives every drug an individual code comprised of letters and numbers
The first letter indicates the therapeutic system C =
cardiovascular system, N = nervous system
The next numbers and letters specify the group and finally the specific drugN05A = antipsychotics, N05AA = phenothiazine with aliphatic side chain, N05AA01= chlorpromazine
Gives also defined daily doses (DDD) Gives also the consumption of drugs as the DDD per 1000 inhabitants
per day, calculated from the number of wholesale sales to pharmacies
FATAL POISONINGS ACCORDING TO THE MOST IMPORTANT FINDING IN 2003-2005
2003 2004 2005 C Cardiac glycosides 5 4 9 Beta blocking agents 23 36 28 Other 12 4 5 N Antiepileptics 10 4 13 Antipsychotics 77 70 86 Anxiolytics 15 15 14 Barbiturates 0 0 1 Antidepressants 107 151 123 Hypnotics and sedatives 37 29 49 Opioids 132 135 126 Other analgesics 4 5 8 Other drugs 36 37 39 All 458 490 501
THE MOST COMMON DRUGS IN FATAL POISONINGS IN FINLAND 2003-2005
2003 2004 2005 Amitriptyline 37 48 46 Codeine 47 44 45 Levomepromazine 29 32 38 Buprenorphine 33 35 32 Zopiclone 15 16 30 Doxepin 21 25 22 Tramadol 21 21 21 Propranolol 12 15 14 Alprazolam 10 11 13 Dextropropoxyphene 14 15 12 Insulin 8 8 12 Temazepam 17 10 12 Chlorprothixene 12 8 11 Quetiapine 2 3 11 Venlafaxine 9 14 11 Citalopram 11 13 10 Digoxin 5 4 9 Mirtazapine 9 14 9 Oxycodone 7 11 9 Metformin 8 3 7 Olanzapine 6 5 7
ESTIMATION OF FATAL TOXICITY
Different methods have been used to relate the
deaths by poisoning to the consumption of drugs
since 1974 The ”fatal toxicity index” by Cassidy and Henry (1987) is
defined as the ratio of the number of deaths divided
by the number of prescriptions (in millions) or by the
number of standard quantity units prescribed or by
the weight of drug prescribed. The ”fatality rate” by Farmer and Pinder (1989) is the
number of deaths divided by the estimated number of
prescriptions (in millions) The ”fatality ratio” by Vuori et al. (1989) is defined as
fatalities divided by DDD per 1000 inhabitants per day
ESTIMATION OF FATAL TOXICITY, CONT.
Fatal poisonings depend on the intrinsic toxicity and
availability of drugs. By controlling drug availability, it is possible to
compare intrinsic toxicity. In general, different estimations give a similar ranking
of drugs in fatal poisonings, whether calculated
against the number of prescriptions or the sales of
drugs. Limitations
If the number of prescriptions is used, over-the-counter drugs cannot be included.
Indices cannot be calculated for drugs of abuse that are also available on the streets
THE MOST DANGEROUS CATEGORY OF DRUGS IN FINLAND IN 2004
ATC code
Group of drugs Sales Deaths Fatality ratio
C01A Cardiac glycosides 6.59 4 0.61 N03A Antiepileptics 11.5 4 0.35 N05A Antipsychotics 16.7 70 4.19 N06A Antidepressants 56.7 151 2.66
THE MOST DANGEROUS DRUG IN FINLAND IN 2004
Drug Sales Deaths Fatality ratio
Propranolol 1.91 15 7.85 Metoprolol 18.6 10 0.54 Bisoprolol 20.2 7 0.35 Alprazolam 7.73 11 1.42 Temazepam 19.0 10 0.53 Oxazepam 7.77 3 0.39 Trimipramine 0.31 10 32.3 Doxepin 1.05 25 23.8 Amitriptyline 3.80 48 12.6 Melperone 0.17 8 47.1 Levomepromazine 0.80 32 40.0 Clorprothixene 0.69 8 11.6
THE FATALITY INDEX OF SOME HYPNOTICS AND SEDATIVES IN 2002-2005
DDD 2002 2003 2004 2005 Zopiclone, deaths 38 15 16 30 Zopiclone, sales 7.5 mg 26.4 27.8 27.1 26.9 Zopiclone, fatality ratio 1.44 0.54 0.59 1.12 Zolpidem, deaths 2 2 3 4 Zolpidem, sales 10 mg 4.59 5.28 5.78 6.11 Zolpidem, fatality ratio 0.44 0.38 0.52 0.65 Temazepam, deaths 11 17 10 12 Temazepam, sales 20 mg 18.7 19.3 19.0 18.5 Temazepam, fatality ratio 0.59 0.88 0.53 0.65 Oxazepam, deaths 2 1 2 1 Oxazepam, sales 50 mg 7.85 7.84 7.77 7.69 Oxazepam, fatality ratio 0.25 0.13 0.26 0.13
CASE: PROMAZINE
1998 1999 2000 2001 2002 2003 2004 Promazine, deaths 38 45 61 43 20 8 1 Promazine, sales 0.37 0.39 0.38 0.34 0.28 0.05 - Promazine, fatality ratio (FR) 103 115 160 126 71.4 - - Levomepromazine, deaths 40 60 35 43 34 29 32 Levomepromazine, sales 0.96 1.00 0.93 0.90 0.85 0.84 0.80 Levomepromazine, FR 41.7 60.0 37.6 47.8 40.0 34.5 40.0 Olanzapine, deaths - - 1 4 5 6 5 Olanzapine, sales 1.12 1.61 2.22 2.73 3.29 3.83 Olanzapine, FR - - 0.62 1.80 1.83 1.82 1.31
CASE: ANTIDEPRESSANTS IN 2003-2005
Cumulative deats
Cumulative sales
Fatality ratio
Risk ratio
Doxepin 68 3.10 21.9 95 Trimipramine 19 0.92 20.7 90 Amitriptyline 131 11.4 11.5 50 Trazodone 3 0.42 7.14 31 Clomipramine 6 0.87 6.90 30 Venlafaxine 34 10.8 3.14 14 Moclobemide 7 2.29 3.06 13 Mirtazapine 32 16.8 1.91 8 Paroxetine 19 10.6 1.79 8 Fluvoxamine 3 1.74 1.72 7 Sertraline 10 13.7 0.73 3 Citalopram 34 56.7 0.60 3 Fluoxetine 4 17.7 0.23 1
CASE: ANTIDEPRESSANTS IN 2003-2005
Risk ratio
A death per patient years
Doxepin 95 237 Trimipramine 90 256 Amitriptyline 50 452 Trazodone 31 728 Clomipramine 30 754 Venlafaxine 14 1,657 Moclobemide 13 1,718 Mirtazapine 8 2,721 Paroxetine 8 2,889 Fluvoxamine 7 3,016 Sertraline 3 7,248 Citalopram 3 8,697 Fluoxetine 1 23,600
ANTIDEPRESSANTS: WHY DO THEY BEHAVE DIFFERENTLY?
Not because of poor analytics The unit DDD per 1000 inhabitants per day is
calculated based on the sales from pharmacies Some antidepressants are prescribed for other
indications than depression Prescription habits: Are the drugs selected according
to severity of depression or to different types of
patients? The intrinsic toxicity of the drugs varies.
ALCOHOL – DRUG INTERACTIONS, STATISTICAL EVALUATION
Alcohol is a frequent finding in post-mortem toxicology. In Finland, about 50% of forensic cases have a BAC >0.5 o/oo
Alcohol has a non-specific membrane effect and shares a specific effect with many drugs via the GABA receptor
Propoxyphene, amitriptyline and barbiturates are known to be more toxic when used together with alcohol
We conducted a study of behavior of ten common drugs together with alcohol and compared the BAC in these cases against pure fatal alcohol poisonings (Koski et al. 2003)
ALCOHOL – DRUG INTERACTIONS
FTIs vs. deviations of median BAC in drug-alcoholpoisonings from that found in pure alcohol poisonings
the bars represent the 95% CIs for the
difference in BAC
SUMMARY
Today, forensic toxicology is not restricted only to
revealing homicides by poisoning, but provides to the
society information that is otherwise difficult or
impossible to obtain. Exploits the results of ”natural experiments” for the
benefit of living human beings. The results can be used to
evaluate drug safety reveal differences in the intrinsic toxicity of drugs and
thereby to rank the drugs reveal the abuse potential of therapeutic drugs follow prescription practices study drug/alcohol or drug/drug interactions on a
statistical basis