Risk of severe driver injury by driving with psychoactive substances.

Driving with alcohol and other psychoactive substances imposes an increased risk of severe injury accidents. In a population-based case-control design, the relative risks of severe driver injury (MAIS≥2) by driving with ten substance groups were approximated by odds ratios (alcohol, amphetamines, benzoylecgonine, cocaine, cannabis, illicit opiates, benzodiazepines and Z-drugs, i.e. zolpidem and zopiclone, medicinal opioids, alcohol-drug combinations and drug-drug combinations). Data from six countries were included in the study: Belgium, Denmark, Finland, Italy, Lithuania and the Netherlands. Case samples (N=2490) were collected from severely injured drivers of passenger cars or vans in selected hospitals in various regions of the countries. Control samples (N=15,832) were sampled in a uniform sampling scheme stratified according to country, time, road type and season. Relative risks were approximated by odds ratios and calculated by logistic regression. The estimates were adjusted for age, gender and country. The highest risk of the driver being severely injured was associated with driving positive for high concentrations of alcohol (≥0.8 g/L), alone or in combination with other psychoactive substances. For alcohol, risk increased exponentially with blood alcohol concentration (BAC). The second most risky category contained various drug-drug combinations, amphetamines and medicinal opioids. Medium increased risk was associated with medium sized BACs (at or above 0.5 g/L, below 0.8 g/L) and benzoylecgonine. The least risky drug seemed to be cannabis and benzodiazepines and Z-drugs. For male drivers, the risk of being severely injured by driving with any of the psychoactive substances was about 65% of that of female drivers. For each of the substance groups there was a decrease in the risk of severe driver injury with increasing age. It is concluded that among psychoactive substances alcohol still poses the largest problem in terms of driver risk of getting injured.

Drugs related to motor vehicle crashes in northern European countries: a study of fatally injured drivers.

The aim of this study was to find which drugs and drug combinations were most common in drivers who died, in particular, in single vehicle crashes where the responsibility for the crash would be referred to the driver killed. The study included all available blood samples from drivers, who died within 24h of the accident, in the years 2001 and 2002 in the five Nordic countries (total population about 24 million inhabitants). The samples were analysed for more than 200 different drugs in addition to alcohol, using a similar analytical programme and cut-off limits in all countries. In three countries (Finland, Norway and Sweden) blood samples were available for more than 70% of the drivers, allowing representative prevalence data to be collected. 60% of the drivers in single vehicle crashes had alcohol and/or drug in their blood samples, compared with 30% of drivers killed in collisions with other vehicles. In single vehicle accidents, 66% of the drivers under 30 years of age had alcohol and/or drugs in their blood (alcohol only - 40%; drugs only - 12%; alcohol and drugs - 14%). The drugs found were mostly illicit drugs and psychoactive medicinal drugs with warning labels (in 57% and 58% respectively of the drivers under 30 with drugs present). Similar findings were obtained for drivers 30-49 years of age (63% with alcohol and/or drugs). In drivers aged 50 years and above, killed in single vehicle crashes (48% with alcohol and/or drugs) illicit drugs were found in only one case, and psychoactive medicinal drugs were detected less frequently than in younger age groups. In 75% of single vehicle crashes, the driver was under 50 years. Thus, the majority of accidents where the drivers must be considered responsible, occurred with drivers who had recently used alcohol, or drugs, alone or in combination. The drugs involved were often illicit and/or psychoactive drugs with warning labels. Therefore a large proportion of single vehicle accidents appear to be preventable, if more effective measures against driving after intake of alcohol and drugs can be implemented.

Screening and quantitative determination of twelve acidic and neutral pharmaceuticals in whole blood by liquid-liquid extraction and liquid chromatography-tandem mass spectrometry.

We describe a multi-method for simultaneous identification and quantification of 12 acidic and neutral compounds in whole blood. The method involves a simple liquid-liquid extraction, and the identification and quantification are performed using liquid chromatography-tandem mass spectrometry. The method was fully validated for salicylic acid, paracetamol, phenobarbital, carisoprodol, meprobamate, topiramate, etodolac, chlorzoxazone, furosemide, ibuprofen, warfarin, and salicylamide. The method also tentatively includes thiopental, theophylline, piroxicam, naproxen, diclophenac, and modafinil, but these drugs were not included in the full validation program and are not described in detail here. Limit of quantitation was 1 mg/kg for the compounds with coefficients of variation of < 20%, except for furosemide, which had a coefficient of variation of 32% at limit of quantitation. The measuring interval was wide for most components. Extraction efficiencies were high, reflecting the high-yield capacity of the method.

The frequency of drugs among Danish drivers before and after the introduction of fixed concentration limits.

OBJECTIVE: Until July 2007, the driving under the influence of drugs (DUID) legislation in Denmark was based on impairment, evaluated on the basis of a clinical investigation and toxicological analyses, but in 2007 fixed concentration limits were introduced into the Danish traffic legislation. The objective for this study was to investigate the prevalence of medication and illicit drugs among Danish drivers before and after 2007. METHODS: Blood samples from drivers suspected of being under the influence of medication and/or illicit drugs were investigated as requested by the police. The results for a 10-year period before and for one year after the introduction of fixed concentration limits are presented. RESULTS: A total of 2340 blood samples were analyzed for the presence of medications and/or illicit drugs for the period 1997-2006. The average number of cases per year was 234 (213-283), and on average 87 percent of the investigated cases were positive for one or more drugs. For 2008 the number of investigated traffic cases was increased to 1176. Seventy-three percent of the cases from 2008 were positive for one or more drugs. Benzodiazepines, cannabis (THC), amphetamine, heroin/morphine, methadone, cocaine, and ecstasy were the most frequently detected drugs for the period 1997-2006 and also in 2008. The number of these cases in which an ethanol level was detected above 0.5 mg/g (the Danish legal limit) was on average 18 percent (9-26%) for the period 1997-2006 and 19 percent for 2008. The average age of the drivers ranged from 31 to 34 years for the period 1997-2006 and was 31 years for 2008. The percentage of females per year ranged from 3 to 20 percent. CONCLUSION: The number of traffic cases investigated for substances other than ethanol were consistently low, in the range of 200 to 300 per year during the period from 1997 to 2006, but after the introduction of fixed concentration limits in 2007 a 5-fold increase was seen already in 2008.

A validated method for simultaneous screening and quantification of twenty-three benzodiazepines and metabolites plus zopiclone and zaleplone in whole blood by liquid-liquid extraction and ultra-performance liquid chromatography- tandem mass spectrometry.

An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) method for detection of 23 benzodiazepines and related compounds in whole blood was developed and validated. The method is used for screening and quantitation of benzodiazepines in whole blood received from autopsy cases and living persons. The detected compounds were alprazolam, bromazepam, brotizolam, chlordiazepoxide, demoxepam, clobazam, clonazepam, 7-aminoclonazepam, diazepam, nordiazepam, estazolam, flunitrazepam, 7-aminoflunitrazepam, lorazepam, lormetazepam, midazolam, nitrazepam, 7-aminonitrazepam, oxazepam, temazepam, triazolam, zaleplon, and zopiclone. Whole blood from drug-free volunteers was used for all experiments. Blood samples (0.200 g) were extracted with ethyl acetate at pH 9. Target drugs were quantified using a Waters ACQUITY UPLC system coupled to a Waters Quattro Premier XE triple quadrupole in positive electrospray ionization, multiple reaction monitoring mode. The use of deuterated internal standards for most compounds verified that the accuracy of the method was not influenced by matrix effects. Extraction recoveries were 73-108% for all analytes. Lower limits of quantification ranged from 0.002 to 0.005 mg/kg. Long-term imprecision (CV%) ranged from 6.0 to 18.7%. We present a fully validated UPLC-MS-MS method for 23 benzodiazepines in whole blood with a run-time of only 5 min and using only 0.200 g of whole blood.

Simultaneous screening and quantification of 29 drugs of abuse in oral fluid by solid-phase extraction and ultraperformance LC-MS/MS.

BACKGROUND: The European DRUID (Driving under the Influence of Drugs, Alcohol And Medicines) project calls for analysis of oral fluid (OF) samples, collected randomly and anonymously at the roadside from drivers in Denmark throughout 2008-2009. To analyze these samples we developed an ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for detection of 29 drugs and illicit compounds in OF. The drugs detected were opioids, amphetamines, cocaine, benzodiazepines, and Delta-9-tetrahydrocannabinol. METHOD: Solid-phase extraction was performed with a Gilson ASPEC XL4 system equipped with Bond Elut Certify sample cartridges. OF samples (200 mg) diluted with 5 mL of ammonium acetate/methanol (vol/vol 90:10) buffer were applied to the columns and eluted with 3 mL of acetonitrile with aqueous ammonium hydroxide. Target drugs were quantified by use of a Waters ACQUITY UPLC system coupled to a Waters Quattro Premier XE triple quadrupole (positive electrospray ionization mode, multiple reaction monitoring mode). RESULTS: Extraction recoveries were 36%-114% for all analytes, including Delta-9-tetrahydrocannabinol and benzoylecgonine. The lower limit of quantification was 0.5 mug/kg for all analytes. Total imprecision (CV) was 5.9%-19.4%. With the use of deuterated internal standards for most compounds, the performance of the method was not influenced by matrix effects. A preliminary account of OF samples collected at the roadside showed the presence of amphetamine, cocaine, codeine, Delta-9-tetrahydrocannabinol, tramadol, and zopiclone. CONCLUSIONS: The UPLC-MS/MS method makes it possible to detect all 29 analytes in 1 chromatographic run (15 min), including Delta-9-tetrahydrocannabinol and benzoylecgonine, which previously have been difficult to incorporate into multicomponent methods.

Blood concentrations of clonazepam and 7-aminoclonazepam in forensic cases in Denmark for the period 2002-2007.

The benzodiazepine clonazepam is a prescription drug used to treat epilepsy and anxiety. In addition, it is frequently used to treat drug addicts and is itself a popular drug of abuse. In this study, we report the incidence and blood concentrations of clonazepam and its metabolite 7-aminoclonazepam in cases referred to the Section of Forensic Chemistry at the University of Copenhagen in 2002-2007. Using LC-MS/MS, clonazepam was detected in 297 traffic cases, 92 criminal cases (perpetrators or victims of a crime) and in 140 postmortem cases. The concentration ranges of clonazepam+7-aminoclonazepam were 0.002-0.840 mg/kg (median 0.067) for traffic cases, 0.005-0.913 (median 0.071) for criminal cases (offenders), 0.002-0.720 (median 0.030) for criminal cases (victims) and 0.002-1.676 (median 0.115) for postmortem cases. The concentrations were thus similar among the groups, although the median value was highest in the postmortem group. In most cases, other drugs were also present. For the postmortem group, the cases (n=27) with relatively high (>0.2 mg/kg) clonazepam+7-aminoclonazepam values were examined in greater detail. Other drugs were present in all cases, with clonazepam judged to be the primary cause of death in five cases. The range of clonazepam+7-aminoclonazepam concentrations in these five cases ranged from 0.26 to 0.54 mg/kg (median 0.29 mg/kg).

[Deaths among drug addicts in Eastern Denmark 2005]. / Dødsfald blandt narkomaner i Østdanmark i 2005.

INTRODUCTION: The purpose of this study was to investigate deaths among drug addicts in Eastern Denmark in 2005, partly fatal poisonings, partly deaths where the cause of death not was a poisoning and to compare the results with those reported in studies from 1991, 1997 and 2002. MATERIAL AND METHODS: All deaths among drug addicts investigated at the Institute of Forensic Medicine in Copenhagen. RESULTS: The number of deaths among drug addicts was 160 of which 64% were due to fatal poisoning. The number of drug addict deaths has remained almost constant in the period 1991-2005, but in 2002 and 2005 a decrease of about 10% was seen in the fraction of fatal poisonings. As in 2002, a decrease in the fraction of heroin/morphine poisonings was seen, and an increase in the fraction of methadone poisonings with a proportion of heroin/morphine poisonings of 17% and a proportion of methadone poisonings of 39%. As in the previous studies, the most commonly detected drugs were methadone, heroin/morphine, benzodiazepines and cannabis and, as in 2002, methadone was more frequently detected than heroin/morphine. In the non-poisoning deaths, the most frequent manner of death was natural death (44%). In 12% the manner of the death was suicide, in 14% death was accidental, in 4% homicide was the manner of death and in 26% the manner of death was undetermined. CONCLUSION: The increase in the number of fatal poisonings with methadone and the decrease in the number of fatal poisonings with heroin/morphine seen in the 2002 study continued in 2005. The poly-drug use had increased in 2005 with more drugs detected in each case than before.

An oxcarbazepine-related fatality with an overview of 26 oxcarbazepine postmortem cases.

We present an oxcarbazepine-related fatality together with an overview of 26 postmortem cases involving oxcarbazepine observed during the period 2001-2006. The fatality case concerned a 27-year-old woman with epilepsy, who was found dead in her bed. Oxcarbazepine and its active metabolite, 10-hydroxycarbazepine, were the only compounds detected. The concentrations of oxcarbazepine were as follows: femoral blood, 2.9mg/kg; muscle, 1.8mg/kg; liver, 0.9mg/kg; gastric content (300ml), 860mg/kg; and vitreous humour, not detected. The concentrations of 10-hydroxycarbazepine were as follows: femoral blood, 66mg/kg; muscle, 40mg/kg; liver, 62mg/kg; gastric content, 27mg/kg; and vitreous humour, 25mg/kg. The analyses were performed by HPLC-DAD after liquid-liquid extraction. Oxcarbazepine intoxication was regarded as a possible cause of death. For the other 26 cases, the 10-hydroxycarbazepine concentrations ranged from 2.2 to 48mg/kg with a median of 25mg/kg.

[Drugs and driving]. / Euforiserende stoffer i trafikken.

In recent years, the problem of driving under the influence of drugs of abuse (DUID) has been subject to increased focus. Several European countries have introduced "zero tolerance" legislation regarding drugs of abuse in traffic. Denmark is currently preparing similar legislation. Epidemiological data suggest that the problem of DUID in Denmark is of similar magnitude as in comparable countries. Relative risk estimations for DUID are reviewed on the basis of recent literature.

[Fatal cases of poisoning in eastern Denmark during a five-year period (1998-2002)]. / Forgiftningsdødsfald over en femårig periode (1998-2002) i Østdanmark.

INTRODUCTION: The goal of this investigation was to determine the pattern of fatal poisonings in eastern Denmark from 1998 to 2002 and compare it with similar investigations from 1979 to 1996. MATERIALS AND METHODS: The material included 2,996 autopsies from eastern Denmark in which extensive forensic chemical investigations were performed. RESULTS: Of the 2,996 autopsies, 694 cases were drug addicts, in whom 497 fatal overdoses were detected, while in the remaining 2,302 cases of nonaddicts, 443 fatal poisonings were determined. Morphine (heroine) and methadone were the main causes of death among the fatal poisonings of the drug addicts, accounting for 90% of the cases. The fatal poisonings among the nonaddicts were due mainly to medicine (73% of the cases); 13% were due to carbon monoxide and/or cyanide poisoning, and 12% were due to acute ethanol poisoning. The medicine was a wide range of strong and weak analgesics, antidepressants and antipsychotic drugs of older and newer origins. Comparison with earlier investigations from 1979 to 1996 showed that the poisoning pattern had changed, but similarities were also seen. The most frequently occurring drugs involved in fatal poisonings in eastern Denmark from 1979 to 2002 were morphine, methadone, ethanol and carbon monoxide/cyanide, of which methadone increased in occurrence over the 23-year period. CONCLUSION: The investigation of fatal poisonings is an important element in monitoring changes in drug abuse and poisoning patterns and levels.

Medicinal and illegal drugs among Danish car drivers.

The objective of this study was to get an insight into the prevalence of medicinal and illegal drugs among car drivers in a Danish rural area. The police randomly stopped about 1000 car drivers and asked them to deliver a saliva sample and gave them a questionnaire to fill in at home. Laboratory analyses by specific methods of samples, which a screening found positive, confirmed that 2% were positive for benzodiazepines or illegal drugs (amphetamine, cannabis, cocaine or opiates): 1.3% were positive for illegal drugs and 0.7% for benzodiazepines. Questionnaire statements from some of the drivers confirm that occasionally some of these drive despite a suspicion to be under the influence of an illegal drug (2.8%), an illegal drug including alcohol (4%), a hazardous medicinal drug including alcohol (8.5%), or alcohol alone above the legal limit (24.5%). These results are considered reliable for the survey area and may not reflect national conditions. The overall results indicate that in this study driving under the influence of illegal drugs or alcohol seems to be associated to especially men, aged 22-44 years. Driving under the influence of hazardous medicinal drugs seems to be associated to middle-aged/elderly drivers, both men and women.