Introduction

Sedative-hypnotic medications impair cognitive and physical functioning, and increase the risk for driver-related road traffic accidents.1 Drivers impaired by benzodiazepines and Z-drugs have difficulty maintaining lane position, regulating speed (driving too fast or slowly), failing to comply with traffic signals, and sustaining attention and reaction time, which lead to road traffic accidents.2 The most widely prescribed classes of sedative-hypnotics are benzodiazepines (eg, lorazepam [Ativan]) and Z-drugs (eg, zopiclone [Imovane]). Benzodiazepines are primarily used in the treatment of anxiety disorders and insomnia, and Z-drugs are generally limited to treating insomnia. Other less-common uses of benzodiazepines include seizure disorders, spasticity, and alcohol withdrawal. While structurally distinct from benzodiazepines, Z-drugs share the same pharmacological and clinical characteristics. Together, these sedative-hypnotics are generally referred to as the benzodiazepine receptor agonists (BZRAs).

Benzodiazepine receptor agonists are not recommended as first-line treatment for anxiety disorders or insomnia.3,4 However, contrary to practice guidelines, they are commonly prescribed as an initial intervention for these indications and frequently transform into chronic use.5,6 Canadian survey data identified the self-reported rate of BZRA use as 4.2% in women and 2.5% in men. Usage rates increase with age (8.5% of older adults versus 2.4% of adults).7 Based on dispensing data, rates of long-term use approximate 7.5%, 11.5%, and 15% of people 60 to 69, 70 to 79, and 80 years of age and older, respectively.5 High prevalence use in older adults has been similarly found in Australia, the United States, and elsewhere.8

Prevalent BZRA usage increased between the 1990 and 2000s, with some evidence of a leveling off or slight reduction in the 2010s. Investigations reveal an overall reduction in benzodiazepine use by older adults (>=65 years old) and no change in use in adults <65 years old.9 In contrast, Z-drug use has increased substantially in adults and older adults.9 Elevated use of BZRAs is of particular concern in older adults who may be more vulnerable to the side effects and adverse reaction profiles of BZRAs. These include injuries from falls,10 dependence and withdrawal,11 memory problems,12 pneumonia,13 sleepwalking and sleep driving,14 and residual effects of the medications that can lead to daytime sedation, which can potentially negatively affect driving performance.2 There is variability in motor vehicle accident fatalities based on age groups: older adult drivers (>=65 years old) drive approximately half the distance of younger drivers (25 to 64 years old),15 but account for twice as many fatal crashes.16 However, the profile of drivers who are more impaired by sedative hypnotics, including BZRAs, may have a lower average age.1,17,18

From a legislative perspective, different countries have different recommendations and laws around the use of these substances and driving. This can range from an "impaired is impaired" standpoint in which, regardless of which substance is ingested,19 impairment due to these drugs can result in prosecution. In some countries, there are established limits in which drug concentration in whole blood is likely to be accompanied by a degree of impairment; however, the legislative limits do not apply to drivers who take medications as prescribed by their physician.20

Patients are encouraged to consult their health care providers on how to safely operate a motor vehicle while consuming BZRAs; however, the information available to health care providers is vague and lacks consensus regarding BZRAs and driving safety. Little is known about how health care providers are counseling patients on how BZRAs affect driving performance. Product monographs are varied in the information they provide regarding safe use of medications and driving. For example, the Canadian Pharmacist Association Monograph for zopiclone indicates in the Occupational Hazards section that health care providers are instructed to "Caution patients that impairment when driving or operating machinery can persist for up to 12 hours after an evening dose. Risk for road traffic crashes appears to be highest during the first 2 weeks of therapy."21 Similar information also appears at the start of the monograph in a Serious Warnings and Precautions box. In the Occupational Hazards section of the monograph for benzodiazepines, health care providers are directed to warn patients about a "[horizontal ellipsis] potential impairment of mental alertness or physical coordination that can affect their ability to perform hazardous tasks such as driving or operating machinery."22 Other commonly used resources by health care professionals make general statements regarding telling patients to not drive until it is safe to do so23 or indicating that patients should not operate a motor vehicle until they know how a medication affects them, especially with dosage changes and new additions of medications.24 However, there is a lack of differentiation in the likelihood of impairment, recognizing the range of half-lives among the BZRAs from one to 100 hours.22 Generally, documents that health care providers may refer to for patient education do not provide specific information regarding how long a patient could expect to be impaired from BZRA consumption or how they know how the medicine affects them and their driving performance.

The lack of available and consistent information regarding driving safety and BZRA consumption is further complicated by the methods used to assess the impact of various BZRAs and driving performance. These vary from laboratory cognitive tests to driving simulators to on-the-road driving tests.25 The tests considered to be of the highest standard are the on-the-road driving tests, and in particular a highly standardized test where subjects are instructed to drive a steady lateral position on a public highway in normal traffic while maintaining a constant speed for 100 km.26 The mean lateral position and the mean speed are continuously recorded, and a standard deviation of lateral position (weaving of the car) and the standard deviation of speed are computed. This test has been shown to demonstrate dose-dependent impairment for alcohol, illicit drugs, as well as some sedative-hypnotic medications, antidepressants, and antihistamines.27 Driving simulators range from fully interactive systems using instrumented vehicles with 360-degree view to desktop systems. They are capable of assessing higher level behaviors in a safe and controlled manner, however, are criticized for limited realism.25 Lastly, laboratory cognitive tasks permit an assessment of a single isolated aspect of driving performance in a controlled environment. However, these are limited in their validity to compare to real-life driving and are questionable in whether they can be accurately used to predict accident risk.25

A preliminary search of PROSPERO, MEDLINE, the Cochrane Database of Systematic Reviews, and the JBI Database of Systematic Reviews and Implementation Reports was conducted and no current or in-progress systematic reviews on the topic were identified.

The purpose of this scoping review is to identify the methodologies used to assess the impact of individual BZRAs on driving performance. A scoping review methodology is necessary to identify opportunities for future data synthesis and identify research gaps. These data will serve as a component of the evidence base to be used for developing guidance related to the safe use of BZRAs and driving.

Review question

How have the effects of individual BZRAs been assessed on people's motor vehicle driving performance?

Inclusion criteria

Participants

This review will consider studies that include participants who are new, intermittent, or chronic users of BZRAs. No exclusions will be applied regarding the health status of participants or whether their BZRA use is for an approved indication as indicated by government agencies (eg, Health Canada) or practice guidelines. Factors such as age, presence of comorbidities, or other known risk factors for poor driving performance will be tabulated in the data extraction. Subjects will be of age to be licensed to operate a motor vehicle. Study subjects in hospital or residing in long-term care or assisted living facilities will not be considered in this review.

Concept

The current scoping review will consider studies in which there is a demonstrated or inferred presence of a BZRA in association with the operation of a motor vehicle (eg, cars, trucks, motorcycles). Operation of a motor vehicle may be real or simulated. Outcomes may include direct or indirect objectives or standard subjective measures or indicators of impairment while operating a motor vehicle. Studies that retrospectively link outcomes, such as traffic accidents to exposure to BZRAs, will be considered in addition to controlled prospective trials.

Context

The current scoping review will consider studies that have been conducted to study the effect of BZRAs on driving performance in a variety of settings, including community-based settings; urban, rural, and remote settings; and international settings.

Types of sources

This scoping review will consider experimental studies, quasi-experimental study designs, and observations studies. Specific examples of study designs include randomized controlled trials, non-randomized controlled trials, before and after studies, cohort and case-control studies, cross-sectional studies, case series, and case studies. Systematic reviews meeting the inclusion criteria will also be considered.

Methods

The proposed scoping review will be conducted in accordance with JBI methodology.28,29

Search strategy

The search strategy will aim to locate both published and unpublished studies. An initial limited search of MEDLINE (Ovid) and Embase (Elsevier) was undertaken to identify articles on the topic. To identify benzodiazepine keywords for the search, benzodiazepines listed in various drug monograph databases (eg, Micromedex, Lexicomp, and Martindale: The Complete Drug Reference) were searched. The text words contained in the titles and abstracts of relevant articles, and the index terms used to describe the articles were used to develop a full search strategy in MEDLINE (see Appendix I). The search strategy, including all identified keywords and index terms, will be adapted for each included information source. The reference lists of all studies selected for inclusion will be screened for additional studies. Only studies published in English will be included. No date limits will be applied.

The databases to be searched for published research include EMBASE (Elsevier), MEDLINE (Ovid), and PsycINFO (EBSCO). The search for unpublished studies will include ProQuest Dissertations and Theses (ProQuest) and trial registers including ClinicalTrials.gov, EU Clinical Trials Register (ClinicalTrialsRegister.eu), International Clinical Trials Registry Platform, and Cochrane Central Register of Controlled Trials. Initial keywords to be used will be "benzodiazepine," "sedative-hypnotic," "Z-drug," "driving impairment," and "driving performance."

Gray literature (eg, policy documents and legislation on driving and medication use, vital statistics) will be used during the scoping review process to provide background information, contextualize the issues, and identify application of findings for clinical and policy settings. Other gray literature will not be searched given that the scoping review question focuses on the body of evidence evaluating the methods of driving performance and BZRAs.

Study selection

Following the search, all identified citations will be collated and uploaded into Covidence 2019 (Veritas Health Innovation, Melbourne, Australia) and duplicates removed. Using Covidence, titles and abstracts will then be screened by two independent reviewers for assessment against the inclusion criteria for the review. The full text of selected citations will be assessed in detail against the inclusion criteria by two independent reviewers using Covidence. Reasons for the exclusion of full-text studies that do not meet the inclusion criteria will be recorded and reported in the scoping review. Any disagreements that arise between the reviewers at each stage of the study selection process will be resolved through discussion or with a third reviewer. The results of the search will be reported in full in the final scoping review and presented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.30 Included studies will be retrieved in full and their citation details imported into JBI System for the Unified Management, Assessment and Review of Information (JBI SUMARI; JBI, Adelaide, Australia).31

Data extraction

Data will be extracted from papers included in the scoping review by two independent reviewers using the draft data extraction tool provided in Appendix II. The data extracted will include specific details about the population (eg, age, presence of comorbidities), study design, date published, sample size, location of study, BZRAs studied (inclusive of dosing regimen), measures of impairment (eg, accident, road-side assessment, driving simulation, driving test), and key findings relevant to the review objective. The draft data extraction tool will be modified and revised as necessary during the process of extracting data from each included study. Modifications will be detailed in the full scoping review report.

Data analysis and presentation

The extracted data will be presented in diagrammatic or tabular form in a manner that aligns with the objective of this scoping review. A narrative summary will accompany the tabulated and/or charted results and will describe how the results relate to the review's objective and question. The findings will be discussed as they relate to practice and research.

Acknowledgments

Kristy Hancock, who at the time of writing the protocol was at the W.K. Kellogg Health Sciences Library, Dalhousie University, for her assistance developing and running the searches.

Funding

Student research support was provided to SMP by the Drug Evaluation Alliance of Nova Scotia (DEANS). The funder providing the student research support was not involved in the design, data collection and analysis, decision to publish, or preparation of the manuscript.

Appendix I: Search strategy

MEDLINE (Ovid)

Date searched: November 14, 2019

Number of results: 1310

(((Automobile Driving/ or motor vehicles/ or automobiles/ or motorcycles/ or (Automobile^* or car or cars or truck^* or motorcycle^* or motor cycle^* or motor vehicle^* or vehicle^* or traffic or driver^* or driving or crash or crashes or crashing or collision^*).ti,ab,kw,kf.) and ((Impair^* or drug^* or intoxicat^* or under the influence or somnolen^* or fatigue^* or sleep^* or drows^* or hungover or hangover^* or drunk^*).ti,ab,kw,kf. or Fatigue/) and ("hypnotics and sedatives"/ or sleep aids, pharmaceutical/ or Tranquilizing Agents/ or Anti-Anxiety Agents/ or benzodiazepines/ or alprazolam/ or bromazepam/ or clonazepam/ or exp diazepam/ or flunitrazepam/ or flurazepam/ or lorazepam/ or nitrazepam/ or oxazepam/ or prazepam/ or temazepam/ or chlordiazepoxide/ or clobazam/ or clorazepate dipotassium/ or estazolam/ or medazepam/ or midazolam/ or triazolam/ or Eszopiclone/ or Nordazepam/ or Zolazepam/ or Zolpidem/ or exp GABA Agonists/ or (Sleep medication^* or sleep aid^* or hypnotic drug^* or hypnotic agent^* or sleep promoting agent^* or sedative-hypnotic^* or benzodiazepine^* or benzodiazepinone^* or anxiolytic^*).ti,ab,kw,kf. or ((anxiolytic^* or anti anxiety or anti-anxiety or antianxiety or ataractic^*) adj2 (agent^* or drug^*)).ti,ab,kw,kf. or (minor adj2 tranquiliz^*).ti,ab,kw,kf. or ((Benzodiazepine or gaba) adj3 (agonist^* or receptor^* or stimulant^* or stimulator^* or stimulating or agent^*)).ti,ab,kw,kf. or (benzodiazepine adj2 derivative^*).ti,ab,kw,kf. or (alprazolam or bromazepam or brotizolam or clonazepam or cloxazolam or chlordiazepoxide or clobazam or chlorazepate or cinolazepam or clotiazepam or delorazepam or diazepam or estazolam or eszopiclone or etizolam or flunitrazepam or fludiazepam or flutazolam or flutoprazepam or flurazepam or halazepam or haloxazolam or Ketazolam or loprazolam or lorazepam or lormetazepam or midazolam or medazepam or mexazolam or nitrazepam or nimetazepam or nordazepam or oxazepam or Oxazolam or prazepam or phenazepam or pinazepam or quazepam or temazepam or tetrazepam or triazolam or tofisopam or zolazepam or zapizolam or zopiclone or zaleplon or zolpidem or bzra).ti,ab,kw,kf.)) or (((Driver^* or driving) adj3 (health or behavio?r^* or abilit^* or perform^* or accident^* or crash or crashes or crashing or injur^* or collision^* or fatalit^* or safety or risk^* or fatigue^* or attention or inattention or sleep^* or drows^* or alert or alertness or fitness or assess^* or evaluat^*)).ti,ab,kw,kf. or ((Road^* or highway or motorway or traffic) adj3 (accident^* or crash or crashes or crashing or injur^* or collision^* or fatalit^* or safety or risk^* or fatigue^* or attention or inattention or sleep^* or drows^* or alert or alertness or fitness or assess^* or evaluat^*)).ti,ab,kw,kf or (fitness to drive or fitness-to-drive).ti,ab,kw,kf. or driving under the influence/ or Accidents, Traffic/) and ("hypnotics and sedatives"/ or sleep aids, pharmaceutical/ or Tranquilizing Agents/ or Anti-Anxiety Agents/ or benzodiazepines/ or alprazolam/ or bromazepam/ or clonazepam/ or exp diazepam/ or flunitrazepam/ or flurazepam/ or lorazepam/ or nitrazepam/ or oxazepam/ or prazepam/ or temazepam/ or chlordiazepoxide/ or clobazam/ or clorazepate dipotassium/ or estazolam/ or medazepam/ or midazolam/ or triazolam/ or Eszopiclone/ or Nordazepam/ or Zolazepam/ or Zolpidem/ or exp GABA Agonists/ or (Sleep medication^* or sleep aid^* or hypnotic drug^* or hypnotic agent^* or sleep promoting agent^* or sedative-hypnotic^* or benzodiazepine^* or benzodiazepinone^* or anxiolytic^*).ti,ab,kw,kf. or ((anxiolytic^* or anti anxiety or anti-anxiety or antianxiety or ataractic^*) adj2 (agent^* or drug^*)).ti,ab,kw,kf. or (minor adj2 tranquiliz^*).ti,ab,kw,kf. or ((Benzodiazepine or gaba) adj3 (agonist^* or receptor^* or stimulant^* or stimulator^* or stimulating or agent^*)).ti,ab,kw,kf. or (benzodiazepine adj2 derivative^*).ti,ab,kw,kf. or (alprazolam or bromazepam or brotizolam or clonazepam or cloxazolam or chlordiazepoxide or clobazam or chlorazepate or cinolazepam or clotiazepam or delorazepam or diazepam or estazolam or eszopiclone or etizolam or flunitrazepam or fludiazepam or flutazolam or flutoprazepam or flurazepam or halazepam or haloxazolam or Ketazolam or loprazolam or lorazepam or lormetazepam or midazolam or medazepam or mexazolam or nitrazepam or nimetazepam or nordazepam or oxazepam or Oxazolam or prazepam or phenazepam or pinazepam or quazepam or temazepam or tetrazepam or triazolam or tofisopam or zolazepam or zapizolam or zopiclone or zaleplon or zolpidem or bzra).ti,ab,kw,kf.)) not (exp Animals/ not Humans/)

Appendix II: Data extraction tables

Table A: Which drugs have been tested using which tests?

Table B: Time of dosing (evening vs middle of night) and time of day testing (morning vs afternoon) effect on driving for each drug and at what dose

References