Beitske E. Smink

The Relationship between Benzodiazepine Use and Traffic Accidents: A Systematic Literature Review

In many countries, benzodiazepines are the most commonly used and misused psychoactive medicinal drugs. Results of epidemiological studies investigating the association between benzodiazepine use and traffic accidents seem to be inconclusive or inconsistent at first sight. However, the outcome of epidemiological studies may be influenced by several methodological factors like study design, study population, exposure measurement, outcome definitions and possible confounders.Our objective was to conduct a systematic literature review of epidemiological studies that investigated the association between benzodiazepine use and traffic accidents, including related outcomes like culpability and injury or accident severity. We searched EMBASE, PubMed and Forensic Science Abstracts 3/0 (FORS®) for references included in these databases at 1 June 2009 using the term ‘benzodiazepines’ in combination with ‘driving performance’ or ‘accident risk’ or ‘traffic accident’. For inclusion in this review, the study design had to be comparative, include road users involved in accidents and provide specific data about benzodiazepines. Sixty-six studies were included in the review. The study populations varied from the general (driving) population, accident-involved road users with or without injury and persons admitted to a hospital to fatally injured accident-involved drivers. Exposure assessment was performed by using toxicological results, prescription data or questionnaires.The divergent study populations and comparison groups and the variety of methods used to express the outcome of interest hampered comparison between results.Evidence is growing that exposure to benzodiazepines is related to increased accident risk. The literature indicates that the greatest accident risk is associated with the use of long half-life benzodiazepines, increasing dosage and the first few weeks of use of benzodiazepines. Clear evidence of increased culpability associated with benzodiazepine use is scarce. More research has to be done to elucidate the relationship between benzodiazepine use and injury severity.

An analytical evaluation of eight on-site oral fluid drug screening devices using laboratory confirmation results from oral fluid

The performance of eight on-site oral fluid drug screening devices was studied in Belgium, Finland and the Netherlands as a part of the EU-project DRUID. The main objective of the study was to evaluate the reliability of the devices for testing drivers suspected of driving under the influence of drugs (DUID). The performance of the devices was assessed by their ability to detect substances using cut-offs which were set at sufficiently low levels to allow optimal detection of positive DUID cases. The devices were evaluated for the detection of amphetamine(s), cannabis, cocaine, opiates and benzodiazepines when the relevant test was incorporated. Methamphetamine, MDMA and PCP tests that were included in some devices were not evaluated since there were too few positive samples. The device results were compared with confirmation analysis results in oral fluid. The opiates tests appeared to perform relatively well with sensitivity results between 69 and 90%. Amphetamines and benzodiazepines tests had lower sensitivity, although the DrugWipe test evaluated was promising for amphetamine. In particular, it is evident that the cannabis and cocaine tests of the devices still lack sensitivity, although further testing of the cocaine tests is desirable due to the low prevalence and low concentrations encountered in this study.

Driving under the influence of alcohol and/or drugs in the Netherlands 1995–1998 in view of the German and Belgian legislation

This study presents the test results of blood and urine samples of impaired drivers in the Netherlands between January 1995 and December 1998. In this period, the blood alcohol concentrations of 11,458 samples have been determined and 1665 blood or urine samples have been analysed for drugs. The median alcohol concentration was between 1.7 and 1.8 mg/ml blood. In 80% of the 1665 analysed samples drugs were detected. At least 42% (702/1665) of the impaired drivers were poly-drug users, with cocaine present in the most frequent combinations. In the Netherlands, the procedure to prove driving under the influence is complex. This procedure can be made more efficient and more effective by embedding the analytical test results, needed to prosecute an impaired driver, in the law. In Belgium and Germany, such laws already are in force. If we would apply the qualifications of the new Belgian law on our analytical data, 67% of the impaired drivers included in this comparison could have been prosecuted without discussion in court.

The concentration of oxazepam and oxazepam glucuronide in oral fluid, blood and serum after controlled administration of 15 and 30 mg oxazepam

AIMS To measure and compare the concentration-time profiles of oxazepam and oxazepam glucuronide in blood, serum and oral fluid within the scope of roadside testing. METHODS Biological samples were collected from eight male subjects after ingestion of 15 or 30 mg oxazepam on separate dosing occasions with an interval of 7 days. The concentration-time profiles of oxazepam and oxazepam glucuronide were fitted by using a one-compartment model. RESULTS For oxazepam and oxazepam glucuronide, the mean oral fluid/blood ratios were 0.05 (range 0.04-0.07) and 0.004 (range 0.002-0.006), respectively. The concentration-time profiles in oral fluid paralleled those in blood. CONCLUSION After oral administration of therapeutic doses of oxazepam, concentrations in oral fluid are very much lower than those in blood, and those of oxazepam glucuronide are much lower than those of the parent compound. Nevertheless, assay of oral fluid for oxazepam can be used to detect recent ingestion of the drug in drivers suspected of impaired driving performance.

The Relation Between the Use of Psychoactive Substances and the Severity of the Injury in a Group of Crash-Involved Drivers Admitted to a Regional Trauma Center

Objective. There is much evidence that driving under the influence of alcohol and/or drugs of abuse is related to an increased accident risk. A remaining question is whether the use of psychoactive substances is also related to clinically more severe accidents. The aim of this study is to explore the relationship between the use of psychoactive substances and the injury severity in a group of crash-involved drivers. Methods. The study group included all injured car drivers, admitted to the regional trauma center, in the period from May 2000 until August 2001. The outcome of interest was the severity of injury, measured by using the Injury Severity Score (ISS). The determinant was the presence of psychoactive substances in blood and urine samples. Psychoactive substances tested for were alcohol, amphetamines, barbiturates, benzodiazepines, cannabis, methadone, opiates, and tricyclic antidepressants in blood and urine. Results. The number of injured car drivers included in this study was 106. Overall, 43% (46/106) of the drivers tested positive for at least one psychoactive substance. Comparison of the means of the log ISS suggests that there is no significant difference between drivers who tested positive for alcohol and/or drugs, compared to drivers tested negative. Conclusion. The results of this study support the hypothesis that there is no clear association between use of psychoactive substances and the severity of crash-related injury.

The relation between the blood benzodiazepine concentration and performance in suspected impaired drivers

Several experimental studies have shown a negative influence of benzodiazepines on driving skills. The objective of this study is to study the relationship between the blood concentration of benzodiazepines and the influence on performance in field sobriety tests. A retrospective case file evaluation was conducted to select cases of drivers, tested positive for benzodiazepines only in the period from January 1999 to December 2004. Drivers were grouped into the categories sub therapeutic, therapeutic or elevated concentrations. The outcome of the tests (walking, walking after turn, nystagmus, Rombergs test, behavior, pupils and orientation) was binomial. A Chi square test was used to assess differences in proportions of the categorized cases. In total 171 cases were included. Observations of behavior (n=137; p<0.01), walking (n=109; p<0.01), walking after turn (n=89; p=0.02) and Rombergs test (n=88; p<0.05) were significantly related to the benzodiazepine concentration. There was no significant relation between benzodiazepine concentration and effect on pupil size, nystagmus or orientation. The results of our study indicate a relation between the concentration of benzodiazepines and the results of some performance tests. More effort is needed to standardize the tests and to determine the sensitivity and selectivity of the tests for benzodiazepines.

Repeatability of oral fluid collection methods for THC measurement

STUDY OBJECTIVES To determine the influence of sample collection for two different collection methods on THC concentrations and to compare THC concentrations collected by both methods. METHODS A total of 136 pairs of oral fluid samples from subjects who had recently smoked Cannabis were obtained by the non-acidic Statsure oral fluid collection device and by ordinary spit tubes. Oral fluid was analyzed for THC by LC-MS/MS. Bland-Altman plots were used for the quantitative analysis of repeatability, whereas Cohens kappa was used for qualitative analysis to determine the consistency of the results with regard to the Belgian legal limit. RESULTS Repeatability of both sampling methods was very low. The Statsure device had a better rate of agreement when compared with the Belgian legal limit than the spitting method. THC concentrations of samples collected by spit tubes were on average a factor 5.9 higher than the corresponding concentrations in samples collected by the Statsure device. CONCLUSIONS The repeatability of both the Statsure collection method and the ordinary spit tubes was low when applied to subjects who had consumed Cannabis very recently. Furthermore, THC concentrations were higher in samples obtained by spitting than samples collected with Statsure. These results may have implications for confirmation analysis in oral fluid, when applied for legal purposes.

Prevalence of medicinal drugs in suspected impaired drivers and a comparison with the use in the general Dutch population

The aim of this study was to investigate the prevalence of psychotropic medicines in drivers suspected of driving under the influence of medicinal and illicit drugs in The Netherlands and to compare the prevalence of selected impairing medicines with the use of these medicines in the general Dutch population. In total, 3038 blood samples of suspected impaired drivers in The Netherlands have been analyzed for the presence of medicinal and illicit drugs between January 2009 and December 2012. In 94% (2842/3038) of the cases medicinal and/or illicit drugs were detected. Medicinal drugs were found in 33% of the blood samples, with the highest prevalence for anxiolytics. In 86% of the cases illicit drug-positive results were obtained, with the highest prevalence for cannabis. At least in 56% of the blood samples poly-drug use was determined, including medicinal and/or illicit drugs. The highest prevalence of poly-medicine use was found for combinations including anxiolytic and hypnotic drugs. In general, the prevalence of driving impairing medicines in suspected impaired drivers is higher than the use of these medicines in the general Dutch population, due to a positive selection bias in the first population. Differences between both populations may be explained by the used methodological approach (e.g., classification criteria of analytical findings, sample selection bias) and abuse of certain medicinal drugs (e.g., diazepam). Negative effects of medicinal drugs on driving performance determine largely the prevalence in the population of suspected impaired drivers. The degree of impairment depends on different factors, including pharmacokinetic properties of the drug and pharmacodynamic aspects. More research is needed to study the prevalence of all prescribed driving impairing medicines and to investigate if providing additional information to medicinal drug users on driving impairing medicines would lower the prevalence of medicinal drug positive drivers.

Fatalities, Cerebral Hemorrhage, and Severe Cardiovascular Toxicity After Exposure to the New Psychoactive Substance 4-Fluoroamphetamine: A Prospective Cohort Study

Study objective: We study adverse health effects after use of the new psychoactive substance 4‐fluoroamphetamine. Methods: All patients who reported 4‐fluoroamphetamine exposure and for whom the Dutch Poisons Information Center was consulted by their physician in 2016 were included in a prospective cohort study. The clinical course was investigated through telephone interviews with the physician and/or patient, using standardized questionnaires. 4‐Fluoroamphetamine was analyzed in remaining drug material and biological samples with liquid and gas chromatography–mass spectrometry techniques. Results: We included 45 patients, and follow‐up with the physician and/or patient was performed in 33 cases. All patients experienced adverse effects after 4‐fluoroamphetamine use. Severe toxicity was reported in 8 patients. In 5 of these patients, 4‐fluoroamphetamine exposure was confirmed in biological specimens. Severe toxicity that was reported included 2 fatalities, 4 patients with cerebral hemorrhage (1 fatal), 2 patients with inverted Takotsubo’s cardiomyopathy, 1 patient with myocardial infarction, 1 patient with acute heart failure, and an overall high prevalence of pronounced hypertension and tachycardia. Conclusion: Since the introduction of 4‐fluoroamphetamine to the Dutch drug market in 2007, its use continues to increase, possibly because users perceive it as “ecstasy light” and thus relatively safe. However, the proportion of patients with severe toxicity after 4‐fluoroamphetamine use is relatively large in our study population. Therefore, users should be warned about the risks of 4‐fluoroamphetamine.

The relationship between drug use and traffic accident severity

The use of alcohol and certain illicit and psychoactive medicinal drugs has been associated with impaired driving and increased accident risk. Data with respect to the relationship between drug use and the severity of the accident, independent of the increased accident risk, are limited. The objective of this chapter is to evaluate and discuss the available epidemiological studies on the relationship between drug use by drivers and the severity of the accident. Data sources used for the literature search were EMBASE, PubMed and Forensic Science Abstracts 3/0 (FORS®). All databases were searched for references included in the database on January 1, 2008. Search strategy included the different groups of psychoactive substances of interest and traffic accidents in combination with accident severity or injury severity. The number of included publications was 20; they were published between 1983 and 2005. The study population varied from all crash-involved drivers (injured and not injured) to patients admitted to a trauma center (including crash-involved drivers) to fatally crash-involved drivers. The most frequently applied design is the cross-sectional study. In general, exposure assessment was performed by using toxicological results but, in a few studies, prescription data, police officers’ observations or questionnaires were used. The effects reported are controversial, i.e. the influence of psychoactive drugs other than alcohol on injury and/or accident severity is not clear. Some discrepancies may be explained by differences in methodological factors, e.g. study population, injury or accident severity measures, and exposure measures.