According to the World Health Organization, road injury was the ninth leading cause of death globally between 2002–2012 [
2].The prevalence of prescription-drug–positive fatal motor vehicle accidents has increased by an estimated 49% in the US over the past 20 years, with benzodiazepines in particular more than doubling their rate of involvement in such accidents [
3]. In Canada, 11.2% of drivers killed in vehicle accidents between 2000 and 2010 tested positive for sedative-hypnotic prescription drugs post-mortem [
4]. For the past decades, benzodiazepines and Z-drugs have been the focus of much public safety research, both epidemiological and experimental, on motor vehicle driving performance and outcomes.
3.1 Pharmacological Basis and Experimental Studies
Experimental studies have involved administration of a sedative-hypnotic medication to individuals prior to a measured test of driving performance, be it simulated or in an actual vehicle. Though experimental study designs may differ, many studies have utilized a common, validated measure of safe driving performance called the standardized deviation of lateral position (SDLP); an index of maintaining vehicle positioning while driving on a stretch of road (usually straight) at a constant speed [
5]. A 2009 meta-analysis by Rapoport et al. carefully selected five on-road experimental studies of similar methodology to determine differences in SDLP between benzodiazepine users and controls with a reported pooled estimate of standardized mean difference (SMD) between groups of 0.80 (
p = 0.0004) at
a ≤5-mg dose equivalent of diazepam [
6]. The SMD further increased to 3.07 standard deviations at
a ≥10-mg diazepam dose equivalent, thus implying a dose-dependent loss of vehicle control in users compared with controls [
6]. Another meta-analysis of 14 randomized controlled trials by Roth et al. in 2014 concluded that driving performance diminished significantly with longer half-life agents, higher doses, and when time between single dosing and driving was reduced [
7]. Furthermore, based on some studies, blood plasma concentrations of benzodiazepines in impaired drivers has been shown to correlate, with some degree of reliability, with risk of potential accidents [
8,
9]. For instance, the presence of benzodiazepine in blood samples from 818 drivers (159 not impaired, 659 impaired) yielded an adjusted odds ratio for determination of driving impairment of 1.60 for mildly elevated concentrations and 3.75 for highly elevated concentrations [
9].
Z-drugs in particular have also been the subject of experimental studies, although less so than benzodiazepines. A pooled analysis of four studies on zopiclone’s potential for residual sedation contributing to driving risk demonstrated that impairment lasted for up to 11 hours after dosing, was not significantly dependent on sex or age, and was comparable in magnitude to a blood alcohol concentration of up to 0.8 mg/L, which, in turn, corresponds to at least twice the risk of motor-vehicle accidents [
10]. Perhaps because of this, zopiclone has been used as a positive control for studies on other drugs in driving because of its reliability in causing significant impairment [
11]. Studies on zolpidem and zaleplon in healthy subjects have not been shown to cause significant residual impairment leading to traffic accident risk with early or middle-of-the-night dosing [
12‐
15]. Zolpidem has been shown to cause significant changes in SDLP, standard deviation in speed, and alertness in healthy drivers between the ages of 55–65 years [
16]. A literature review by Gunja also ranks zopiclone over the other Z-drugs in terms of potential for residual impairment, but also places rightful emphasis on safety concerns arising from sleep behaviors (including sleep driving) reported more frequently in zolpidem users [
17]. A simplified, summative, evidence-based categorization guide produced by the International Council on Alcohol, Drugs and Traffic Safety (ICADTS) has ranked various medications based on their potential for causing impaired driving (I = presumed safe, II = minor to moderate impairment, III = severe impairment), with 22 benzodiazepines and zopiclone ranked at III and nine benzodiazepines, zolpidem, and zaleplon ranked at II [
18,
19].
3.2 Epidemiologic Studies
Epidemiological studies examining real-world accident outcomes, as opposed to experimental surrogate outcomes (SDLP and others), are perhaps easier to place into relevant context for clinicians and those in public health. Twenty-five of 28 epidemiological studies examined in a review by Gjerde et al. found positive associations between road traffic accidents and benzodiazepine/Z-drugs [
20]. Smink et al., in a 2010 systematic review, examined 66 studies published between 1960 and 2009 of varying methodologies [
21]. However, interpretation of the studies was partially hampered due to the extremely divergent study designs, populations, exposure measurement methods, and outcome measures assessed for the included studies. Nonetheless, the authors concluded that risk is greatest with higher dosages, longer half-life agents, and within the first few weeks of drug initiation [
21].
In terms of quantifying this association, the meta-analysis by Rapoport et al. also provided pooled odds ratio estimates for case–control studies (
n = 6) and cohort studies (
n = 3) on accident risk with benzodiazepine exposure, reporting a 60% higher odds of accident in benzodiazepine users [
6]. Another 2011 meta-analysis by Dassanayake et al. also included an assessment of benzodiazepine association with motor vehicle accidents via three distinct pooled odds ratio estimates based on case–control studies (
n = 6, OR = 1.59), cohort studies (
n = 3, OR = 1.81), and accident culpability studies (
n = 5, OR = 1.41), all of which significantly indicated an association [
22]. The last estimate, on accident culpability, when considered in conjunction with the experimental studies, strengthens the causal argument by showing that those involved in vehicle accidents who consumed benzodiazepine medication were ~40% more likely to be at fault than the other parties involved. The latest 2013 meta-analysis by Elvik separated pooled risk estimates by outcome (fatal, injury, or property damage) rather than by study type for benzodiazepines [
23]. For benzodiazepines, after adjusting for publication bias, these estimates remained significant for fatal accidents (
n = 10, OR = 2.30), injury accidents (
n = 51, OR = 1.17), and property damage (
n = 4, OR = 1.35) [
23].
The epidemiologic association made between Z-drugs and motor vehicle accidents is less robust than with the benzodiazepines yet is still significant enough to warrant concern among clinicians, public health researchers, and policy makers. Studies of differing methodologies and sample populations have reported overall risk/odds ratios ranging from a 38% increased risk/odds to over double the risk/odds of traffic accidents in zolpidem users over non-users [
24‐
27]. Despite the compelling experimental evidence for driving impairment, the epidemiological evidence for zopiclone in vehicle accidents is less clear, as some studies have found an association [
28,
29] and others have not [
27]. An exhaustive 2016 systematic review of epidemiologic studies on numerous medications and motor vehicle collisions by Rudisill et al. found four of five studies to be statistically significant for zolpidem and two of six studies to be statistically significant for zopiclone [
30].
Although sedative-hypnotic drugs undoubtedly seem to pose a hazard in driving safety, increased risk has been tentatively identified in certain users or medication-related behaviors, albeit with much uncertainty. Younger age [
22,
28] and new use of benzodiazepines [
26] have been reported as additional risk factors in users of these medications. A literature review on gender risk difference in drugged driving has found that, with the exception of zolpidem and flurazepam, no differences in impairment have been noted between the sexes, but this has been foremost due to a lack of study data differentiating the magnitude of impairment between men and women [
31]. An observational study finding suggests that drug impaired driving, in some jurisdictions, may be primarily among a younger population using these medications non-medically with or without the concurrent use of illicit street drugs [
32]. This raises the question as to what proportion of vehicle crashes associated with sedative-hypnotics is from irresponsible or non-medical use as opposed to use as prescribed. Driving and drug-taking behavior among younger drivers is likely sufficiently different enough for confounding to have played some role in these associations. Further to this, others have speculated that the increased risk observed among younger drivers is partially owed to a combination of factors including reduced life experience with these drugs leading to an underestimation of impairment effect, higher doses routinely received, and a relative absence of competing risk factors (poorer health status etc.) making modest risk differences attributable to benzodiazepines more easily detectible in comparison [
22,
33].
Despite the general consensus among the literature, some other overall limitations warrant mention regarding many of the epidemiological studies on this association. Foremost, is confounding by indication, whereby sleep deprivation increases accident risk independent of drug use [
34]. This is especially the case for studies defining exposure by only receipt of prescription rather than toxicologic confirmation of drug use or patient testimony. Furthermore, many retrospective designs are incapable of reliably establishing a sufficient causal context for each recorded traffic accident in no small part due to biases (patient or investigator) or lack of pertinent information relating to driving incidents. For example, a particular traffic accident may have taken place long after the cessation of a drug’s sedative effect, making exposure purely coincidental but nevertheless resulting in a false-positive accident captured within study results.
3.3 Summary
There is an overwhelming degree of evidence, both experimental and epidemiological, implicating benzodiazepines in particular, but Z-drugs as well, with fatal and non-fatal motor vehicle accidents. Though some limitations and discrepancies persist, both streams of evidence (experimental and epidemiological), when considered together, support a strong causal argument for exposure of these drugs resulting in motor vehicle accidents. It seems more research is necessary to elucidate with certainty which medications, at what doses, and in which patients increases risk beyond an acceptable degree so as to enable effective targeted interventions to reduce motor vehicle harm.