Beitske E. Smink

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.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Concentration–time profiles of drugs in oral fluid generally run parallel to those in blood.• In general, oral fluid contains more parent drug than metabolites.• For some benzodiazepines it has been shown that concentrations are lower in oral fluid than in blood. WHAT THIS STUDY ADDS • The concentration–time profile of oxazepam in oral fluid after a single dose of oxazepam runs parallel to blood and is dose dependent.• Concentration ratios (oral fluid/blood and oral fluid/serum) of oxazepam and oxazepam glucuronide after controlled intake of a single dose of oxazepam are presented.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.

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.

Benzodiazepines are the most frequently detected medicinal drugs in drivers. The use of benzodiazepines is associated with an increased road accident risk. In this study, the presence of benzodiazepines detected by liquid chromatography-(tandem) mass spectrometry [LC-MS(-MS)] in oral fluid and urine samples obtained from drivers stopped during a roadside survey was compared. In addition, the sensitivity and selectivity of enzyme multiplied immunoassay technique (EMIT^® II Plus) relative to LC-MS(-MS) was determined for both matrices. A total number of 1011 urine samples were collected and screened for benzodiazepines using immunoassay (IA) (EMIT II Plus; cutoff 300 ng/mL). In the IA-positive (n = 25) and a group of randomly selected negative urine samples (n = 79), the presence or absence of benzodiazepines was confirmed by LC-MS-MS after deglucuronidation. The corresponding oral fluid samples (n = 101, 3 samples omitted), were analyzed by LC-MS(-MS) and IA (EMIT II Plus; cutoff 10 ng/mL). The presence of benzodiazepines was demonstrated by LC-MS-(MS) in all IA-positive urine samples, but in only four corresponding oral fluid samples. Concentrations in oral fluid were, one substance excepted, lower than in urine. The sensitivity and specificity of EMIT II Plus were better by using urine as matrix for screening of benzodiazepines than by using oral fluid. The results show that benzodiazepines are detectable in oral fluid. More research has to be done to determine the pharmacokinetic profile of the different benzodiazepines in oral fluid and to study the relationship between dose, concentration (in oral fluid and blood), and impairment.