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