The Relationship Between Blood Benzodiazepine Concentration and Vehicle Crash Culpability. Marie C Longo1 , Robert J Lokan2 and Jason M White 3 1
2
Doctoral candidate, Department of Clinical and Experimental Pharmacology, Adelaide University, Adelaide, S.A., Australia 5005
Principal Forensic Scientist, Forensic Science, Department for Administrative and Information Services, 21 Divett Place, Adelaide, S.A., Australia 5000 3
Professor, Department of Clinical and Experimental Pharmacology, Adelaide University, Adelaide, S.A., Australia 5005
ABSTRACT
INTRODUCTION
Objective: The purpose of this study was to determine the relationship between blood benzodiazepine concentration and crash risk.
A concentration-dependent relationship has been established between alcohol and crash risk, with the risk of crash involvement increasing at higher blood alcohol concentrations (BACs) (Borkenstein et al., 1964; McLean & Holubowycz, 1981). Moreover, studies have consistently reported that a significantly higher percentage of alcohol-positive drivers are culpable for their crashes, and this effect is more marked at higher BACs (Terhune, 1982; Terhune et al., 1992; Drummer, 1994). Based on this evidence, legal guidelines have been instituted which define the concentration above which it is illegal to drive a vehicle.
Methods: Blood samples from 2500 injured drivers were analyzed for benzodiazepines and the relationship between concentration and crash risk was assessed using culpability analysis. Benzodiazepine concentrations were expressed as a proportion of the peak concentration of the drug in blood or plasma for a standard therapeutic dose of the drug. Results: There were 68 drivers (2.7%) who tested positive for at least one benzodiazepine. Of these, 16 (23.5%) also tested positive for alcohol. Drivers who tested positive for benzodiazepines, either alone or in combination with alcohol, had a higher culpability rate than drug-free drivers. There was a significant linear relationship between benzodiazepine concentration and culpability for drivers who tested positive for benzodiazepines alone. Conclusion: The results here provide clear evidence of increased culpability associated with benzodiazepine use, which was marked at higher concentrations.
Received 12/222000 Accepted: 1/22/2001 Email:
[email protected]
The benzodiazepine class comprises many individual drugs, some with active metabolites. The various benzodiazepines do not differ markedly with respect to their pharmacodynamics, but there are pharmacokinetic differences resulting in variations in their time course of action. For example, benzodiazepines such as oxazepam and temazepam are short acting with halflives of around 8 hours, and do not form active metabolites (Greenblatt et al., 1975; Bittencourt et al., 1979). Conversely, diazepam has a half-life of around 48 hours, and its active metabolite nordiazepam has a half-life ranging from 50-99 hours (Kaplan et al., 1973a). The benzodiazepines also vary considerably in the doses administered for therapeutic purposes and the resulting blood concentrations observed. Prior research examining the relationship between benzodiazepine use and crash risk has yielded inconsistent results, with some studies finding no significant relationship (Jick et al., 1981; Benzodiazepine Collaborative Group, 1993; Leveille et al., 1994). Conversely, other studies have found a strong relationship between prescription of a benzodiazepine and crash risk (Skegg et al., 1979; Ray et al., 1992; Neutel, 1995). However, as these authors
examined prescription rather than use, there are a number of confounding factors that limit their conclusions. There have been three studies to date that have used culpability analysis to assess the relationship between benzodiazepine use and crash risk. This method is based on the premise that if drugs do contribute to crashes, the proportion of drivers who are judged culpable will be greater among drug-positive drivers than drug-free drivers. The results have been inconsistent: one study found that benzodiazepine positive drivers had a higher culpability rate than drugfree drivers (Drummer, 1994) and another found the reverse (Terhune, 1982), although the differences were not statistically significant. In the third study there was no difference in culpability (Terhune et al., 1992). However, the number of drivers in each of these studies who tested positive for benzodiazepines alone was small as most also tested positive for alcohol, and the results must be interpreted with caution. Only one of these studies examined the relationship between benzodiazepine concentration and culpability (Terhune, 1982). Drug concentrations were rated from 1 (indicating a low therapeutic concentration) to 3 (indicating a high, non-therapeutic concentration). Although the drugs were usually detected at low therapeutic concentrations, all drivers with medium or high concentrations of benzodiazepines were culpable. In order to better define the relationship between benzodiazepine use and crash risk, it is necessary to analyze blood samples from a very large sample of crash-involved drivers and also to develop a scale of benzodiazepine concentration that takes into account the diverse compounds in this class. The present study used a sample of 2500 injured drivers from whom blood samples were collected and crash details recorded. A scale of concentration was developed using the proportion of the Cmax (peak concentration of the drug in blood or plasma) for a standard therapeutic dose of each drug. The relationship between this proportion and crash culpability was then determined.
SUBJECTS AND METHODS Sample selection and procedure Under Section 47(i) of the Road Traffic Act (1961) of South Australia, any person over the age of 14 years who attends one of 70 prescribed hospital Accident & Emergency units following a road crash must provide a blood sample. Blood samples are collected from all such drivers who attend these hospitals after being involved in a non-fatal road crash, and who survive more than 30 days. For the present study, consecutive samples were collected in the periods April 1995 to August 1995, and December 1995 to August 1996. These samples were analyzed for alcohol,
tetrahydrocannabinol stimulants.
(THC),
benzodiazepines
and
Analytical methods Whole blood samples were initially screened for the presence of benzodiazepines by radioimmunoassay. Double Antibody Serum Benzodiazepine kits purchased from Diagnostic Products Corporation, California, USA were used without modification. Although raised against oxazepam, the antiserum cross-reacts sufficiently to detect all common benzodiazepines and their metabolites qualitatively. A nominal apparent level of 5 ng/mL was adopted as the cut-off value. The positive blood samples were retained for subsequent confirmation of drug identity and accurate quantification. Individual benzodiazepine drugs within the generic class were identified by single-step solvent extraction followed by analysis using capillary gas chromatography with electron capture detection or high pressure liquid chromatography with scanning UV absorption detection, depending on the chemical structure of the drug. Identification was based on comparison of the determined retention time with those of authentic drug standards run concurrently. Quantification was carried out by the same technique and employing prazepam as the internal standard and appropriately spiked blood samples carried through the procedure as calibrators. The approximate limits of detection were 5 ng/mL for diazepam, nordiazepam, clonazepam, alprazolam and nitrazepam, 10 ng/mL for desalkylflurazepam, bromazepam, 7-amino-clonazepam and midazolam, and 100 ng/mL for oxazepam and temazepam. Details of the analytical methods used for alcohol, THC and stimulants are given in Longo et al. (2000a). Culpability analysis The culpability of the injured driver in each crash was assessed by identifying any mitigating factors that may have reduced responsibility for the crash. A driver was judged culpable if not exonerated by these mitigating factors. If sufficient mitigating factors were identified, a driver was deemed only partly culpable (contributory) or not culpable. The analysis was based on eight mitigating factors: the condition of the road, the condition of the vehicle, general driving conditions, the type of crash, witness observations, road law obedience, the difficulty of the task involved and the level of fatigue. A full description of this method has been reported elsewhere (Robertson and Drummer, 1994). Cmax values Mean Cmax values for standard therapeutic doses of benzodiazepines were obtained from published sources. However, for some drugs information was only
available on the Cmax in plasma. The whole blood benzodiazepine concentrations were converted to plasma concentration equivalents using the plasma to whole blood ratio for each drug (see Table 1). There was no information on this ratio, or on the Cmax value in blood, for alprazolam. It is thus possible that the Cmax proportion reported for this drug concentration is unreliable as it is based on the concentration in whole blood. However, this was unlikely to have affected the analysis as only one driver tested positive for alprazolam, and this driver also tested positive for diazepam. Tables 2 and 3 show the mean benzodiazepine concentrations found in whole blood before Cmax values were obtained, for benzodiazepines alone or in combination with other drugs. Ten cases were excluded from the culpability analysis. One was a truck driver who was excluded as factors related to culpability and likelihood of injury will be different from car drivers and motorcycle riders. Two drivers were assigned a ‘contributory’ culpability score, which means that drivers were not solely responsible for the crash and that other factors may have contributed. The remaining seven cases were excluded as the time delay between the crash and blood sample collection was either unknown, or greater than six hours. Most benzodiazepines used outside hospital settings have very long half-lives, either as the parent compound or as the active metabolite or both. For this reason time delays of a few hours are unlikely to result in marked differences in benzodiazepine concentration between the time of the crash and blood sample collection. Accordingly, only those drivers where the delay was greater than six hours were eliminated. For this group the possible confounding effect of drug intake during the intervening period is most likely and the difference in concentration due to time delay would be greatest.
RESULTS Prevalence of benzodiazepines A range of benzodiazepines was detected in the sample (Table 4). The most common benzodiazepine was nordiazepam (N-desmethyldiazepam), an active metabolite of several benzodiazepines, followed by diazepam, oxazepam and nitrazepam. At least one benzodiazepine was detected in 68 drivers (2.7%). Of these, 37 (54.4%) tested positive for one benzodiazepine only. An additional 21 drivers (30.9%) tested positive for two benzodiazepines, eight drivers (11.8%) for three and two drivers (2.9%) for four. However, as some of the benzodiazepine compounds are metabolites, testing positive for more than one drug in this group does not necessarily imply consumption of multiple benzodiazepines by the driver. Concentrations are expressed as a proportion of the therapeutic dose Cmax in Table 4. In the 68 drivers, 44.1% of the
benzodiazepine concentrations (n=30) exceeded the Cmax for a therapeutic dose. Of the 68 drivers who tested positive for benzodiazepines, 16 (23.5%) also tested positive for alcohol. Table 5 shows the range of BACs for these drivers, as well as the distribution of benzodiazepine concentrations in each BAC range. All drivers who tested positive for alcohol and benzodiazepines had a BAC over 0.05%, which is the legal limit in Australia. Moreover, 50% of these drivers had BACs over 0.149%. There were three drivers who tested positive for benzodiazepines in combination with another drug: in one case this drug was methamphetamine and in two cases the drug was THC, the main active component of marijuana. Due to the small number, these three drivers were excluded from subsequent analyses. Benzodiazepine concentration and culpability Figure 1 shows the relationship between benzodiazepine concentration and culpability. Drivers positive for benzodiazepines alone were separated from those who were positive for benzodiazepines in combination with alcohol, and were matched on age with the drug-free group to account for possible differences in culpability due to age. A higher proportion of drivers who tested positive for benzodiazepines were culpable compared with those who were drug-free. When benzodiazepines were used alone, the difference in the proportion of culpable drivers between drug-free and drug-positive groups was statistically significant (χ2 1 =5.7, p=0.017). There was also a significant linear relationship between benzodiazepine concentration and culpability (χ2 1 =8.8, p 1.0
Proportion of the Cmax Benzodiazepines alone Figure 1:
Benzodiazepines in combination with alcohol
Culpability of injured drivers and benzodiazepine concentration expressed as a proportion of the C max: alone or in combination with alcohol
5
Relative risk
4 3 2 1 0 Drug-free
< 0.26
0.26-1.0
> 1.0
Proportion of the Cmax
Figure 2:
Relative risk of culpability for injured drivers and benzodiazepine concentration: benzodiazepines used alone
Table 4: Benzodiazepine detections in injured drivers expressed as a proportion of the Cmax * Type of benzodiazepine Alprazolam
% positive (n=2500) 0.04% (n=1)
Proportion of the Cmax in whole blood or plasma Less than 0.26 (n=1)
Bromazepam
0.08% (n=2)
Clonazepam
0.16% (n=4)
0.08% (n=2)
0.26-1.0 (n=1) More than 1.0 (n=1) Less than 0.26 (n=1) 0.26-1.0 (n=2) More than 1.0 (n=1) More than 1.0 (n=2)
0.04% (n=1)
More than 1.0 (n=1)
Diazepam
1.2% (n=29)
Midazolam
0.08% (n=2)
Less than 0.26 (n=4) 0.26-1.0 (n=8) More than 1.0 (n=17) Less than 0.26 (n=2)
Nitrazepam
0.4% (n=9)
7-amino-clonazepam Desalkylflurazepam
Nordiazepam
+
+
+
Less than 0.26 (n=2) 0.26-1.0 (n=2) More than 1.0 (n=5) Less than 0.26 (n=13) 0.26-1.0 (n=12) More than 1.0 (n=18) Less than 0.26 (n=2) 0.26-1.0 (n=3) More than 1.0 (n=4) Less than 0.26 (n=1) 0.26-1.0 (n=2)
1.7% (n=43)
Oxazepam
0.4% (n=9)
Temazepam
0.1% (n=3)
*In some cases drivers tested positive for more than one benzodiazepine + Metabolite
Table 5: Blood alcohol concentrations of injured drivers testing positive for benzodiazepines BAC (%)
Percentage positive (n=16)
Benzodiazepine concentration as a proportion of the Cmax
0.01 - 0.049
0.0% (n=0)
0.0% (n=0)
0.05 - 0.079
12.5% (n=2)
0.08 - 0.149
37.5% (n=6)
0.150 +
50.0% (n=8)
Less than 0.26 (n=1) More than 1.0 (n=1) Less than 0.26 (n=1) More than 1.0 (n=5) Less than 0.26 (n=1) 0.26-1.0 (n=3) More than 1.0 (n=4)
Mean BAC 0.169% ± 0.068
DISCUSSION Past studies examining the relationship between benzodiazepines and culpability have yielded inconsistent results, as the number of drivers testing positive for benzodiazepines has often been too small to derive meaningful conclusions from the data (Terhune, 1982; Terhune et al., 1992; Drummer, 1994). Moreover, only one study looked at the relationship between benzodiazepine concentration and culpability by classifying concentrations as “low therapeutic”, “high therapeutic” or “non-therapeutic” (Terhune, 1982).
A recent study using the same data set reported in this paper also examined the relationship between benzodiazepine concentration and culpability (Longo et al., 2000). Benzodiazepine-positive drivers were divided into three groups: sub-therapeutic, therapeutic and above therapeutic or toxic. A statistically significant linear relationship was found between benzodiazepine concentration group and culpability. In the present study, these data were reanalyzed using a continuous scale of benzodiazepine concentration expressed as a proportion of the Cmax for a standard therapeutic dose of the drug. The development of a common scale of benzodiazepine concentration enabled
the relationship between drug concentration and crash risk (measured by the culpability of the driver) to be examined as has been done for alcohol. This study used a much larger sample than in past research, increasing the likelihood of statistically significant findings. The results of this study represent clear evidence of increased culpability associated with the benzodiazepine class of drugs. When used alone, there was a significant linear relationship between concentration and culpability. Due to the small sample size, it was not possible to test for linearity when benzodiazepines were used in combination with alcohol, although at higher benzodiazepine concentrations all drivers were culpable. It is possible that the very high levels of alcohol found among this group of benzodiazepine-positive drivers may explain the significant increase in culpability. However, 63% of these drivers had benzodiazepine concentrations exceeding the Cmax, and it is unlikely that this increase in culpability was due to the presence of alcohol only. Experimental studies have found that the effect of this drug combination is generally additive, and that impairment is greater as the concentrations increase (Linnoila et al., 1990; Moskowitz and Burns, 1977 ). When interpreting these data, it is important to note that there was no information available on drivers’ history of benzodiazepine use, such as the dose taken prior to the crash or the frequency of use. Experimental studies have found that a tolerance to the impairing effects of benzodiazepines occurs after chronic use (Ghoneim et al., 1981). Epidemiological research has found that first-time users of benzodiazepines have a significantly higher risk of crash involvement within two months of first filling a prescription for a benzodiazepine, compared with controls (Neutel, 1995). Crash risk is also found to increase with increasing dose, and with the use of more than one benzodiazepine (Ray et al., 1992). Moreover, the use of benzodiazepines with a long half-life has been associated with a significant increase (almost 50%) in crash risk irrespective of duration of exposure, although the risk was slightly lower after continuous use for up to one year. Conversely, there was no such elevated risk for drivers using benzodiazepines with a short half-life (Hemmelgarn et al., 1997). The approach used here to establish a scale of benzodiazepine concentration is a unique one. While it was effective in establishing a concentration-culpability relationship, its limitations should be recognized. In particular, the Cmax values are averages only and do not account for individual differences in factors such as age or weight. Additionally, the Cmax values for the different benzodiazepines are based on approximately equivalent therapeutic doses. However, because of differences in pharmacokinetics, it is not possible to determine exact equivalents.
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